CN100354265C - Pharmaceutical compounds - Google Patents

Abstract

Anthranilic acids and the pharmaceutically acceptable salts thereof of formula (I):wherein R to R9 is an organic substituent, n is 0 or 1, m is 0 or an integer of 1 to 6, q is 0 or 1, X is a direct bond, O, S, -S-(CH2)p or -O-(CHO2)p- wherein p is from 1 to 6 and Ar is an unsaturated carbocyclic or heterocyclic group, have activity as inhibitors of P-glycoprotein and may thus be used, inter alia, as modulators of multidrug resistance in the treatment of multidrug resistant cancers, for example to potentiate the cytotoxicity of a cancer drug.

Description

Anthranilic acid derivative and preparation method thereof and as the purposes of multiple resistance conditioning agent

The present invention relates to (MDR), particularly compound, their preparation method and the medicinal and veterinary composition that contains them of the conditioning agent of the MDR that causes by the excess generation of P-glycoprotein (P-gp) as multiple resistance (multi-drug resistance).

Tumour is the obstacle of cancer patients's success chemotherapy to the resistance of some cell toxicity medicament treatment.Tumour can be used to former treatment Cytotoxic drugs deposits yields resistance.Tumour also can demonstrate inherent resistance or crossed resistance to the cell toxicity medicament that did not occur in the past, the used any medicine of these cell toxicity medicaments and former oncotherapy on structure or mechanism of action without any related.

Similarly, some pathogenic agent can obtain resistance to former treatment by disease or the disorderly medicine that these pathogenic agent produce.Pathogenic agent also can demonstrate inherent resistance or crossed resistance to the medicine that did not occur in the past.The example of this effect comprises the multiple resistance form of malaria, tuberculosis, leishmaniasis and Entamoeba histolytica.These phenomenons are referred to as multiple resistance (MDR).

P-gp excess on the most general form cytolemma of MDR produces and causes that P-gp can reduce a kind of protein of medicine accumulative in cell by medicine is pumped.Shown this kind protein be multiple drug-fast major cause in the tumour cell (Beck, W.T.Biochem.Pharmacol, 1987,36,2879-2887).

Except that cancer cell, also in the many health adult tissues that comprise liver, small intestine, kidney and blood-brain endothelium, find P-glycoprotein.P-gps is positioned the emiocytosis zone in all these tissues.This location shows that P-gp works in the absorption of restriction external source toxicant by biological barrier.

Therefore, except that they can increase the ability of susceptibility of cancer cell pair cell cytotoxic drug, expection P-gp inhibitor can increase the oral clean absorption of some drugs and improve the transhipment of medicine by blood brain barrier.Shown really to give Cyclosporin A that promptly a kind of P-gp inhibitor can increase the absorption (Tereo of rat to acebutolol and vincaleucoblastine 2.6 and 2.2-intestines doubly respectively, T. etc., J.Pharm.Pharmacol, 1996,48,1083-1089), and the mouse that lacks this kind P-gp gene demonstrates susceptibility (Schinkel, A.H. etc., Cell1994 up to 100 times of increases to nervus centralis poison sterilant ivermectin, 77,491-502).Except that increasing brain Chinese traditional medicine level, show that also mouse that P-gp lacks improved drug level and reduced the elimination of medicine in many tissues.

The shortcoming of the medicine of used so far adjusting MDR (being called as resistance conditioning agent or RMA) is that they usually have relatively poor pharmacokinetics aspect pattern and/or have toxicity when MDR regulates required concentration.

Have now found that a series of anthranilic acid derivatives have the activity of P-gp inhibitor, therefore can be used for overcoming the multiple resistance of tumour and pathogenic agent.They also can be used for improving absorption, distribution, the metabolism of some drugs and eliminate characteristic.

Therefore the invention provides compound or its pharmacy acceptable salt into the anthranilic acid derivative of formula (I):

Wherein

R, R ¹And R ², can be identical or different, H, C respectively do for oneself ₁-C ₆Alkyl, OH, C ₁-C ₆Alkoxyl group, halogen, nitro or N (R ¹⁰R ¹¹) R wherein ¹⁰And R ¹¹Can be identical or different, H or C respectively do for oneself ₁-C ₆Alkyl, or R ¹And R ²Be connected ring bThe consecutive position on common methylene-dioxy or the ethylenedioxy of forming;

R ³Be H or C ₁-C ₆Alkyl;

R ⁴Be C ₁-C ₆Alkyl or R ⁴Representative-CH ₂-or-CH ₂CH ₂-, it or encircle with (i) b2 link to each other to form one with ring bThick and saturated 5-or 6-unit contain azo-cycle, or with (ii) the ring aLast phase ortho position is connected with one of continuous formation in position and the ring of a singly-bound X aThick and saturated 5-or 6-unit contain azo-cycle;

R ⁵Be H, OH or C ₁-C ₆Alkyl;

X be direct key, O, S ,-S-(CH ₂) _p-or-O-(CH ₂) _p-, wherein p is the integer of 1-6;

R ⁶Be H, C ₁-C ₆Alkyl or C ₁-C ₆Alkoxyl group;

Q is 0 or 1;

Ar is undersaturated carbocyclic ring or heterocyclic group, wherein undersaturated heterocyclic group be selected from furans, thiophene, pyrroles, indoles, isoindole, pyrazoles, imidazoles, different _ azoles, _ azoles, isothiazole, thiazole, pyridine, quinoline, quinoxaline, isoquinoline 99.9, thieno-pyrazine, pyrans, pyrimidine, pyridazine, pyrazine, purine and triazine group, it is not replace or replaced by one or more substituting group, for example by one or more C that is selected from OH, halogen, does not replace or replace ₁-C ₆Alkyl is as being replaced as CF by halogen ₃, C ₁-C ₆Alkoxyl group, nitro and amino N (R as defined above ₁₀R ₁₁) replace;

R ⁷And R ⁸Can be identical or different, the H that respectively does for oneself, do not replace or by 1,23 C that halogen atom replaces ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, hydroxyl, halogen, phenyl ,-NHOH, nitro, N (R as defined above ¹⁰R ¹¹) or SR ¹²R wherein ¹²Be H or C ₁-C ₆Alkyl, in the time of maybe on being positioned at adjacent carbons, R ⁷And R ⁸The carbon atom that links to each other with them forms phenyl ring or methylene-dioxy substituting group;

R ⁹Be phenyl or undersaturated heterocyclic radical, wherein undersaturated heterocyclic group be selected from furans, thiophene, pyrroles, indoles, isoindole, pyrazoles, imidazoles, different _ azoles, _ azoles, isothiazole, thiazole, pyridine, quinoline, quinoxaline, isoquinoline 99.9, thieno-pyrazine, pyrans, pyrimidine, pyridazine, pyrazine, purine and triazine group; Wherein any one is all unsubstituted or by C ₁-C ₆Alkyl, OH, C ₁-C ₆Alkoxyl group, halogen, C ₃-C ₆Cycloalkyl, phenyl, benzyl, trifluoromethyl, nitro, ethanoyl, benzoyl or N (R as defined above ¹⁰R ¹¹) replace, or locational two substituting groups of the adjacent ring of this phenyl or heterocyclic radical form saturated or undersaturated 6-unit ring together, or form methylene-dioxy;

N is 0 or 1;

M is 0 or the integer of 1-6.

X is connected in ring aOn not by R ⁶Any one of the 2-6 position that occupies.Preferably it is connected on 3 or 4.In preferred a series of compounds, R ⁶At ring a2 and X at 3 or 4.When X is encircling a3 or 4 when going up, R ⁶Can select to occupy 5.Because ring aRotate freely, 6 with 2 equivalences.

The m value is preferably 0 or the integer of 1-3, and more preferably 1 or 2.The q value is preferably 1.

C ₁-C ₆Alkyl can be linear or side chain.C ₁-C ₆Alkyl generally is C ₁-C ₄Alkyl is as methyl, ethyl, propyl group, sec.-propyl, normal-butyl, sec-butyl or the tertiary butyl.Halogen is F, Cl, Br or I.Preferred halogen is F, Cl or Br.The C that replaces ₁-C ₆Alkyl is generally replaced by one or more halogen atom, as being replaced by 1,2 or 3 halogen atom.This alkyl can be a whole haloalkyl, as trifluoromethyl.

C ₁-C ₆Alkoxyl group can be linear or side chain.It generally is C ₁-C ₄Alkoxyl group is as methoxyl group, oxyethyl group, propoxy-, isopropoxy, positive propoxy, n-butoxy, sec-butoxy or tert.-butoxy.M is the integer of 1-6, generally is 1,2 or 3.

Undersaturated carbon ring group generally is the C that contains at least one unsaturated link(age) ₅-C ₁₀Carbon ring group, C for example ₆-C ₁₀Aryl such as phenyl or naphthyl.The unsaturated heterocycle group generally is 5 or the 6-unit heterocycle that contains at least one unsaturated link(age), and it contains the heteroatoms of one or more N of being selected from, S and O, and optional and phenyl ring or second such 5 or 6-unit heterocycle thick with.

Preferred R ⁹The heterocyclic group of representative comprises at least one nitrogen-atoms, and preferably includes at least one nitrogen-atoms or sulphur atom by the heterocyclic group of Ar representative.

In preferred a series of compounds, n is 0, R ⁴Representative-CH ₂CH ₂-, it and ring b2 or 6 link to each other and with ring bForm a tetrahydroisoquinoline group.Perhaps, n is 1, R ⁴Representative-CH ₂-, it and ring b2 or 6 link to each other and with ring bForm a tetrahydroisoquinoline group.

In another preferred a series of compounds, m is 1, and X is connected in ring a3 or 4 singly-bound, and R ⁴Representative-CH ₂-, it respectively with ring aContiguous 3 or 4 ring position links to each other and encircles together aForm a tetrahydroisoquinoline group.Perhaps, m is 0, and X is connected in ring a3 or 4 singly-bound, and R ⁴Representative-CH ₂CH ₂-, its respectively with ring aContiguous 3 or 4 ring position links to each other and encircles together aForm a tetrahydroisoquinoline group.

Ar partly is preferably benzene, naphthalene, thiophene, thieno-pyrazine, pyridine, pyrazine, indoles or furan nucleus.

R ⁹Be preferably quinoline, isoquinoline 99.9, quinoxaline, pyridine, pyrazine, _ azoles, different _ azoles, thiazole or isothiazole group.More preferably R ⁹Be quinoline-3-base, quinoxaline-2-base, pyrazine-2-base, pyridine-2-base, pyridin-3-yl, _ azoles-4-base or thiazole-4-base.

R, R ¹And R ²Independently be preferably selected from H, OH, C ₁-C ₆Alkoxyl group and nitro, or R is H and R ¹And R ²With ring b2 link to each other with 6 and to form a methylene-dioxy or ethylenedioxy together with 5 or 5 with 4,4 with 3,3.

In aspect preferred, anthranilic acid of the present invention or its pharmacy acceptable salt have following formula (Ia):

R wherein ¹¹And R ²¹Can be identical or different, be respectively hydrogen or methoxyl group;

R ³¹And R ⁴¹Can be identical or different, independently be selected from H, CH separately ₃, CF ₃, F, Cl, Br, NH ₂, NO ₂, NHOH, methoxyl group, hydroxyl and phenyl; Or R ³¹And R ⁴¹When being positioned on the contiguous carbon atom, they form phenyl ring or methylene-dioxy substituting group with the carbon atom that links to each other;

R ⁵¹Be the ring one of among 2-furyl, 3-furyl, 2-thiophene, 3-thiophene, 2-indyl or 2-benzofuryl or following formula (II '), (III ') or (IV '):

R wherein ⁶¹And R ⁷¹Can be identical or different, be selected from the C of hydrogen, linearity or side chain ₁-C ₆Alkyl, C ₃-C ₆Cycloalkyl, phenyl, benzyl, trifluoromethyl, F, Cl, Br, OR ¹², NO ₂, dimethylamino, diethylin, ethanoyl and benzoyl, or R ⁶¹And R ⁷¹When being positioned on the contiguous carbon atom, it forms phenyl ring or methylene-dioxy substituting group with the carbon atom that links to each other;

R ⁸¹And R ⁹¹Can be identical or different, respectively do for oneself hydrogen, methyl or methoxy, or R ⁸¹And R ⁹¹When being positioned on the contiguous carbon atom, they form quinoline or 5,6,7,8-tetrahydroquinoline ring system with the pyridine ring that links to each other;

R ¹⁰¹And R ¹¹¹Can be identical or different, respectively do for oneself hydrogen, methyl or propionyl, or R ¹⁰¹And R ¹¹¹When being positioned on the contiguous carbon atom, they form phenyl ring with the carbon atom that links to each other;

R ¹²¹Be H, C ₁-C ₆Alkyl or C ₃-C ₆Cycloalkyl, phenyl, benzyl or ethanoyl;

R is 0 or 1; With

S is 1,2 or 3.

S is the integer of 1-3, is preferably 1 or 2. in preferred a series of formulas (Ia) compound, and r is 1, and s is 2, R ¹¹And R ²¹All be methoxyl group, R ⁵¹Be 2-quinoxalinyl, 3-quinolyl, 2-pyrazinyl or 3-pyridyl, all these groups all can not replace or be substituted.

On the other hand, anthranilic acid of the present invention has following array structure (A):

Wherein

(a) R, R ¹And R ², can be identical or different, H, OH, NO respectively do for oneself ₂, N (R ¹⁰R ¹¹), halogen or C ₂-C ₆Alkoxyl group, or R is H and R ¹And R ²Coupled carbon atom forms methylene-dioxy or ethylenedioxy together, and condition is R, R ¹And R ²Not all be H; R ³, R ⁵, R ⁶, R ⁷, R ⁸, R ⁹, Ar, X and each self-defined the same formula (I) of m; Or

(b) R, R ¹And R ², can be identical or different, respectively do for oneself H or OMe, R ³, R ⁵, R ⁶, R ⁷, R ⁸, R ⁹, each is self-defined the same for Ar, X and m.

On the other hand, anthranilic acid of the present invention has following array structure (B):

Wherein R, R ¹-R ³, R ⁵-R ⁹, Ar and n define same following formula (I).

On the other hand, anthranilic acid of the present invention has following array structure (C):

Wherein R, R ¹-R ³, R ⁵-R ⁹, Ar, X and m define same following formula (I).

On the other hand, anthranilic acid of the present invention has following array structure (D):

Wherein R, R ¹-R ⁹, Ar, m and n define same following formula (I), X is at ring a3 or 4 on, it defines same following formula (I).

In preferred a series of formulas (I) compound, R ⁴Be C ₁-C ₆Alkyl. preferred R, R ¹And R ²Respectively do for oneself H, OH or methoxyl group.

At ring aOn, R ⁶Can link to each other with arbitrary position of 2-6 position. general R ⁶With ring a2 link to each other.

The preferred examples for compounds of the present invention is as follows.

Chemical name	Compound number
		2-chloro-quinoline-3-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides	9591
The 4-hydroxyl-(2-{4-[2-(6 for 7-fluoroform yl-quinoline-3-formic acid, 7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides	9592
		Quinoline-3-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-is different	9594

Quinoline-2-yl)-ethyl]-the phenyl amino formyl radical }-thiene-3-yl-)-acid amides
		(2-{4-[2-(6 for quinoline-3-formic acid; 7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-4-dimethylamino-phenyl)-acid amides	9595
(2-{4-[2-(6 for quinoxaline-2-formic acid; 7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-4-dimethylamino-phenyl)-acid amides	9596
		(2-{4-[2-(6 for quinoxaline-2-formic acid; 7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-thiene-3-yl-)-acid amides	9597
(3-{4-[2-(6 for quinoxaline-2-formic acid; 7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-pyridine-2-yl)-acid amides	9600
		4-hydroxyl-quinoline-3-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides	9606
(3-{4-[2-(6 for quinoxaline-2-formic acid; 7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-4-methyl-thiophene-2-yl)-acid amides	9608
		(3-{4-[2-(6 for quinoline-3-formic acid; 7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-4-methyl-thiophene-2-yl)-acid amides	9609
Quinoxaline-2-formic acid [2-(4-{2-[(3,4-dimethoxy-benzyl)-methyl-amino]-ethyl }-the phenyl amino formyl radical)-phenyl]-acid amides	9612
		Quinoline-3-formic acid [2-(4-{2-[(3,4-dimethoxy-benzyl)-methyl-amino]-ethyl }-the phenyl amino formyl radical)-phenyl]-acid amides	9613
Quinoxaline-2-formic acid 2-[2-(3,4-dimethoxy-benzyl)-1,2,3,4-tetrahydroisoquinoline-7-base formamyl]-phenyl }-acid amides	9614
		Quinoline-3-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-is different	9615

Quinoline-2-yl)-ethyl]-the phenyl amino formyl radical }-4-first sulfane base (sulfanyl)-phenyl)-acid amides
		Quinoline-3-formic acid (4-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-thiene-3-yl-)-acid amides	9616
(4-{4-[2-(6 for N-; 7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-thiene-3-yl-)-6-methyl-niacinamide	9617
		Quinoline-3-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-second sulfane base]-the phenyl amino formyl radical }-phenyl)-acid amides	9621
Quinoline-3-formic acid (3-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-pyrazine-2-yl)-acid amides	9622
		Quinoline-3-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-oxyethyl group]-the phenyl amino formyl radical }-phenyl)-acid amides	9623
Quinoline-3-formic acid (2-{4-[2-(6,7-dimethoxy-1-methyl-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides	9625
		Quinoline-3-formic acid (2-{4-[2-(1,3-dihydro-isoindole-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides	9626
Quinoline-3-formic acid (2-{4-[2-(6,7-two chloro-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides	9628
		Quinoline-3-formic acid (2-{4-[2-(7,8-two chloro-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides	9629
Quinoline-3-formic acid 2-[4-(2-{[2-(3,4-dimethoxy-phenyl)-ethyl]-methyl-amino }-ethyl)-the phenyl amino formyl radical]-phenyl }-acid amides	9630
		Quinoline-3-formic acid [2-(4-{2-[(3,4-dimethyl-benzyl)-methyl-amino]-ethyl }-the phenyl amino formyl radical)-phenyl]-acid amides	9631
Quinoxaline-2-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-oxyethyl group]-the phenyl amino formyl radical }-phenyl)-acid amides	9632

Quinoline-3-formic acid (2-{3-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides	9633
		Quinoline-3-formic acid (2-{4-[2-(7-nitro-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides	9634
2-methyl-thiazole-4-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides	9635
		Quinoline-3-formic acid [2-(4-{2-[(3,4-dimethoxy-benzyl)-ethyl-amino]-ethyl }-the phenyl amino formyl radical)-phenyl]-acid amides	9636
The 2-methyl-_ azoles-4-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides	9638
		Quinoline-3-formic acid [2-(4-{2-[(3-isopropoxy-4-methoxyl group-benzyl)-methyl-amino]-ethyl }-the phenyl amino formyl radical)-phenyl]-acid amides	9639
Quinoline-3-formic acid [2-(4-{2-[methyl-(3,4,5-trimethoxy-benzyl)-amino]-ethyl }-the phenyl amino formyl radical)-phenyl]-acid amides	9640
		Quinoline-3-formic acid [2-(4-{2-[butyl-(3,4-dimethoxy-benzyl)-amino]-ethyl }-the phenyl amino formyl radical)-phenyl]-acid amides	9641
Quinoline-3-formic acid [2-(4-{2-[(4-butoxy-3-methoxyl group-benzyl)-methyl-amino]-ethyl }-the phenyl amino formyl radical)-phenyl]-acid amides	9642
		Quinoline-3-formic acid [2-(4-{2-[(3,4-two fluoro-benzyls)-methyl-amino]-ethyl }-the phenyl amino formyl radical)-phenyl]-acid amides	9643
Quinoline-3-formic acid [2-(4-{2-[(2; 3-dihydro-benzo [1,4] two oxines-6-ylmethyl)-methyl-amino]-ethyl }-the phenyl amino formyl radical)-phenyl]-acid amides	9645
		Quinoline-3-formic acid [2-(4-{2-[(4-isopropoxy-3-methoxyl group-benzyl)-methyl-amino]-ethyl }-the phenyl amino formyl radical)-phenyl]-acid amides	9646
Quinoline-3-formic acid [2-(4-{2-[(3-hydroxyl-4-methoxyl group-benzyl)-methyl-amino]-ethyl }-the phenyl amino formyl radical)-phenyl]-acid amides	9647
		Quinoline-3-formic acid (2-{4-[3-(6,7-dimethoxy-3,4-dihydro-1H-is different	9648

Quinoline-2-yl)-2-hydroxyl-propoxy-]-the phenyl amino formyl radical }-phenyl)-acid amides
		Quinoline-3-formic acid [2-(4-{2-[(4-hydroxyl-3-methoxyl group-benzyl)-methyl-amino]-ethyl }-the phenyl amino formyl radical)-phenyl]-acid amides	9649
(2-{4-[2-(6 for quinoline-3-formic acid; 7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-2-methyl-phenyl amino formyl radical }-phenyl)-acid amides	9650
		(2-{4-[2-(6 for quinoline-3-formic acid; 7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-2-methoxyl group-phenyl amino formyl radical }-phenyl)-acid amides	9651
Quinoline-3-formic acid [2-(4-{[(3-isopropoxy-4-methoxyl group-benzyl)-methyl-amino]-methyl }-the phenyl amino formyl radical)-phenyl]-acid amides	9652
		5-methyl-pyrazine-2-formic acid (2-{3-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides	9653
(2-{4-[2-(6 for quinoline-3-formic acid; 7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-1-methyl-ethyl]-2-phenyl amino formyl radical }-phenyl)-acid amides	9654
		Quinoline-3-formic acid [2-(4-{2-[(4-dimethylamino-benzyl)-methyl-amino]-ethyl }-the phenyl amino formyl radical)-phenyl]-acid amides	9655
Quinoline-3-formic acid [2-(4-{2-[(3-butoxy-4-methoxyl group-benzyl)-methyl-amino]-ethyl }-the phenyl amino formyl radical)-4,5 dimethoxys-phenyl]-acid amides	9656
		(2-{4-[2-(6 for 5-methyl-pyrazine-2-formic acid; 7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-2-methoxyl group-phenyl amino formyl radical }-phenyl)-acid amides	9657
(2-{4-[2-(6 for pyrazine-2-formic acid; 7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-2-methyl-phenyl amino formyl radical }-phenyl)-acid amides	9658

(2-{4-[2-(6 for pyrazine-2-formic acid; 7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-2-methoxyl group-phenyl amino formyl radical }-phenyl)-acid amides	9659
		Quinoline-3-formic acid (2-{3-[3-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-propyl group]-the phenyl amino formyl radical }-phenyl)-acid amides	9660
N-[2-(4-{[(3-isopropoxy-4-methoxyl group-benzyl)-methyl-amino]-methyl }-the phenyl amino formyl radical)-phenyl]-niacinamide	9661
		Quinoline-3-formic acid [5-chloro-2-(4-{2-[(3,4-dimethoxy-benzyl)-methyl-amino]-ethyl }-the phenyl amino formyl radical)-phenyl]-acid amides	9663
(2-{4-[2-(7 for quinoline-3-formic acid; 8-dihydro-5H-[1; 3] dioxole [4,5-g] isoquinoline 99.9-6-yl also)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides	9664
		Quinoline-3-formic acid (2-{4-[2-(6,7-diethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides	9665
(6-{4-[2-(6 for quinoline-3-formic acid; 7-dimethoxy-3; 4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-thieno-[2,3-b] pyrazine-7-yl)-acid amides	9666
		Quinoline-3-formic acid [2-(4-{2-[(3,4-dimethoxy-benzyl)-methyl-amino]-ethyl }-the phenyl amino formyl radical)-4,5-two fluoro-phenyl]-acid amides	9667
Quinoline-3-formic acid [2-(4-{2-[(3,4-dimethoxy-benzyl)-methyl-amino]-ethyl }-the phenyl amino formyl radical)-5-methyl-phenyl]-acid amides	9668
		Quinoline-3-formic acid [2-(4-{2-[(3,4-dimethoxy-benzyl)-sec.-propyl-amino]-ethyl }-the phenyl amino formyl radical)-phenyl]-acid amides	9669
Quinoline-3-formic acid [2-(4-{2-[(3,4-dimethoxy-benzyl)-methyl-amino]-ethyl }-the phenyl amino formyl radical)-5-nitro-phenyl]-acid amides	9677

2-(4-sec.-propyl-benzamido)-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-benzamide	9304
		2-(4-sec.-propyl-benzamido)-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-6-chloro-benzamide	9405
2-(4-sec.-propyl-benzamido)-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-5-chloro-benzamide	9354
		2-(4-sec.-propyl-benzamido)-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-4-chloro-benzamide	9350
2-(4-sec.-propyl-benzamido)-N-[2-(6,7-dimethoxy-3, dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-3-chloro-benzamide	9401
		2-(4-sec.-propyl-benzamido)-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-5-bromo-benzamide	9394
2-(4-sec.-propyl-benzamido)-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-4-fluoro-benzamide	9349
		2-(4-sec.-propyl-benzamido)-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-3-methyl-benzamide	9398
2-(4-sec.-propyl-benzamido)-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-3-methoxyl group-benzamide	9399
		2-(4-sec.-propyl-benzamido)-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-3-hydroxyl-benzamide	9424
2-(4-sec.-propyl-benzamido)-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-4-nitro-benzamide	9420
		2-(4-sec.-propyl-benzamido)-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-4-amino-benzamide	9435
2-(4-sec.-propyl-benzamido)-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-5-phenyl-benzamide	9432
		3-(4-sec.-propyl-benzamido)-naphthalene-2-formic acid [2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-acid amides	9410

2-(4-dimethylamino-benzamido)-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-benzamide	9256
		2-(4-propyl group-benzamido)-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-benzamide	9297
2-(4-amyl group-benzamido)-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-benzamide	9395
		2-(4-cyclohexyl-benzamido)-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-benzamide	9331
Xenyl-4-formic acid 2-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethylamino formyl radical]-phenyl }-acid amides	9294
		Naphthalene-2-formic acid 2-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethylamino formyl radical]-phenyl }-acid amides	9295
Benzo [1; 3] { 2-[2-(6 for dioxole-5-formic acid; 7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-the ethylamino formyl radical]-phenyl }-acid amides	9302
		2-(4-diethylin-benzamido)-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-benzamide	9310
2-(the 4-tertiary butyl-benzamido)-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-benzamide	9334
		2-benzamido-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-benzamide	9351
2-(4-bromo-benzamido)-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-benzamide	9380
		2-(4-nitro-benzamido)-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-benzamide	9381
2-(4-phenoxy group-benzamido)-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-benzamide	9426
		2-(4-benzoyl-benzamido)-N-[2-(6,7-dimethoxy-3,4-	9427

Dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-benzamide
		2-(4-benzyl-benzamido)-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-benzamide	9442
2-(4-cyclohexyloxy-benzamido)-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-benzamide	9459
		2-(4-benzyloxy-benzamido)-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-benzamide	9460
Pyridine-2-formic acid 2-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethylamino formyl radical]-phenyl }-acid amides	9377
		N-{2-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethylamino formyl radical]-phenyl }-niacinamide	9359
N-{2-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethylamino formyl radical]-phenyl }-Isonicotinamide	9384
		Pyrazine-2-formic acid 2-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethylamino formyl radical]-phenyl }-acid amides	9391
Quinoxaline-2-formic acid 2-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethylamino formyl radical]-phenyl }-acid amides	9347
		Isoquinoline 99.9-1-formic acid 2-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethylamino formyl radical]-phenyl }-acid amides	9383
Quinoline-2-formic acid 2-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethylamino formyl radical]-phenyl }-acid amides	9385
		Isoquinoline-3-carboxylic acid 2-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethylamino formyl radical]-phenyl }-acid amides	9389
Quinoline-3-formic acid 2-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethylamino formyl radical]-phenyl }-acid amides	9397
		Thiophene-3-formic acid 2-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethylamino formyl radical]-phenyl }-acid amides	9365
The 1H-indole-2-carboxylic acid { 2-[2-(6,7-dimethoxy-3,4-dihydro-1H-is different	9367

Quinoline-2-yl)-the ethylamino formyl radical]-phenyl }-acid amides
		Quinoxaline-2-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides	9531
(2-{4-[2-(6 for quinoxaline-2-formic acid; 7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-5-hydroxylamino-phenyl)-acid amides	9542
		(2-{4-[2-(6 for quinoxaline-2-formic acid; 7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-4-methyl-phenyl)-acid amides	9543
(2-{4-[2-(6 for quinoxaline-2-formic acid; 7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-4-hydroxyl-phenyl)-acid amides	9554
		(2-{4-[2-(6 for quinoxaline-2-formic acid; 7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-5-nitro-phenyl)-acid amides	9541
(2-{4-[2-(6 for quinoxaline-2-formic acid; 7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-5-trifluoromethyl-phenyl)-acid amides	9561
		(2-{4-[2-(6 for quinoxaline-2-formic acid; 7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-5-fluoro-phenyl)-acid amides	9562
(2-{4-[2-(6 for quinoxaline-2-formic acid; 7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-3-fluoro-phenyl)-acid amides	9564
		Quinoxaline-2-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-the 4-fluorophenyl)-acid amides	9568
Quinoxaline-2-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-4, the 5-dimethoxy-	9573

Phenyl)-acid amides
		Quinoline-3-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides	9544
Quinoline-3-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-diamino-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-5-fluoro-phenyl)-acid amides	9571
		Quinoline-3-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-4-fluoro-phenyl)-acid amides	9574
(2-{4-[2-(6 for quinoline-3-formic acid; 7-dimethoxy-3; 4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-4,5-dimethoxy-phenyl)-acid amides	9576
		(6-{4-[2-(6 for quinoline-3-formic acid; 7-dimethoxy-3; 4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-benzo [1,3] dioxole-5-yl)-acid amides	9578
(2-{4-[2-(6 for quinoline-3-formic acid; 7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-5-nitro-phenyl)-acid amides	9581
		(2-{4-[2-(6 for quinoline-3-formic acid; 7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-4-methyl-phenyl)-acid amides	9584
(2-{4-[2-(6 for quinoline-3-formic acid; 7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-5-methyl-phenyl)-acid amides	9588
		Quinoline-3-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-4-chloro-phenyl)-acid amides	9593
Quinoline-3-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-5-chloro-phenyl)-acid amides	9586
		Quinoline-3-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-5-amino-phenyl)-acyl	9589

Amine
		Quinoline-2-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides	9545
5; 6; 7; (2-{4-[2-(6 for 8-tetrahydroquinoline-3-formic acid; 7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides	9590
		Pyridine-2-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides	9472
N-(2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-niacinamide	9482
		N-(2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-Isonicotinamide	9483
Pyrazine-2-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides	9493
		5-methyl-pyrazine-2-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides	9527
N-(2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-6-methyl-niacinamide	9557
		N-(2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-6-methoxyl group-niacinamide	9582
(2-{4-[2-(6 for 5-propionyl-pyrazine-2-formic acid; 7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides	9569
		2-benzamido-N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-phenyl }-benzamide	9456
2-benzamido-N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-phenyl }-4-methyl-benzamide	9511
		2-benzamido-N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-is different	9510

Quinoline-2-yl)-ethyl]-phenyl }-5-methyl-benzamide
		2-benzamido-N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-phenyl }-6-methyl-benzamide	9512
2-(2-fluoro-benzamido)-N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-phenyl }-benzamide	9489
		2-(3-fluoro-benzamido)-N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-phenyl }-benzamide	9500
2-(4-fluoro-benzamido)-N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-phenyl }-benzamide	9501
		2-(2,4-two fluoro-benzamidos)-N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-phenyl }-benzamide	9513
2-(2,6-two fluoro-benzamidos)-N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-phenyl }-benzamide	9514
		2-(2-chloro-benzamido)-N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-phenyl }-benzamide	9494
2-(3-chloro-benzamido)-N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-phenyl }-benzamide	9495
		2-(4-chloro-benzamido)-N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-phenyl }-benzamide	9496
2-(2-methyl-benzamido)-N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-phenyl }-benzamide	9497
		2-(3-methyl-benzamido)-N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-phenyl }-benzamide	9503
2-(4-methyl-benzamido)-N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-phenyl }-benzamide	9504
		2-(2-methoxyl group-benzamido)-N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-phenyl }-benzamide	9477
2-(3-methoxyl group-benzamido)-N-{4-[2-(6, the 7-dimethoxy-	9517

3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-phenyl }-benzamide
		2-(4-methoxyl group-benzamido)-N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-phenyl }-benzamide	9518
2-(2-hydroxyl-benzamido)-N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-phenyl }-benzamide	9535
		2-(3-hydroxyl-benzamido)-N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-phenyl }-benzamide	9549
2-(4-hydroxyl-benzamido)-N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-phenyl }-benzamide	9559
		(2-{4-[2-(6 for acetate 2-; 7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-the phenyl amino formyl radical)-phenylester	9534
(2-{4-[2-(6 for acetate 3-; 7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-the phenyl amino formyl radical)-phenylester	9540
		(2-{4-[2-(6 for acetate 4-; 7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-the phenyl amino formyl radical)-phenylester	9548
2-(2-trifluoromethyl-benzamido)-N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-phenyl }-benzamide	9523
		2-(3-trifluoromethyl-benzamido)-N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-phenyl }-benzamide	9524
2-(3-dimethylamino-benzamido)-N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-phenyl }-benzamide	9556
		2-(4-sec.-propyl-benzamido)-N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-phenyl }-benzamide	9447
2-(4-cyclohexyl-benzamido)-N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-phenyl }-benzamide	9461

Naphthalene-1-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides	9470
		Naphthalene-2-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides	9476
2-(3,4-two chloro-benzamidos)-N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-phenyl }-benzamide	9536
		2-(3,4-dimethyl-benzamido)-N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-phenyl }-benzamide	9538
Thiophene-2-carboxylic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides	9471
		Thiophene-3-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides	9492
Furans-3-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides	9526
		The 1H-indole-2-carboxylic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides	9515
Coumarilic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides	9539

2-(4-cyclohexyl-benzamido)-N-[3-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-propyl group]-benzamide	9466
		2-(4-cyclohexyl-benzamido)-N-[2-(3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-benzamide	9479
Quinoxaline-2-formic acid (2-{4-[3-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-propyl group]-the phenyl amino formyl radical }-phenyl)-acid amides	9567
		Quinoxaline-2-formic acid 2-[4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-ylmethyl) phenyl amino formyl radical]-phenyl)-acid amides	9572
Quinoline-3-formic acid (2-{4-[2-(3,4-dihydro-1H-isoquinoline 99.9-2-yl)-second	9577

Base]-the phenyl amino formyl radical }-phenyl)-acid amides
		Quinoline-3-formic acid 2-[4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-ylmethyl)-phenyl amino formyl radical]-phenyl)-acid amides	9585

Formula (I) compound can prepare by the following method, and this method comprises:

(a) with the aminobenzamide of formula (VI)

Wherein Ar, R ⁷And R ⁸Define the samely, Z is with the lower section:

Wherein m, n, q, R, R ¹-R ⁶And the X definition is the same, uses formula R ⁹The carboxylic acid of-COOH or its activated derivatives are handled, wherein R ⁹Define the same; Or

(b) with formula XII compound:

Wherein Ar, R ⁵, R ⁶-R ⁹, X, q and m definition is the same, handle with the amine of formula XX:

Wherein R, R ¹-R ⁴The same with the n definition; And the protecting group of removable any optional existence if desired; and/or if desired; a kind of formula (I) compound can be changed into another kind of formula (I) compound and/or; if desired; one place's formula (I) compound can be changed into its pharmacy acceptable salt and/or; if desired, salt can be changed into free formula (I) compound.

In method mutation (a), carboxylic acid R ⁹-COOH can commercially obtain or can be according to preparing below with reference to the explanation among the embodiment 6A.This acid can be activated into corresponding acyl chlorides R ⁹It can or pass through-COCl. free carboxy acid R by the commerce acquisition ⁹-COOH handles and makes with thionyl chloride.Perhaps, carboxylic acid R ⁹-COOH can use cyclohexyl-N-(2-morpholino ethyl)-carbodiimide methyl-right-tosylate and I-hydroxybenzotriazole, or with iodate 2-chloro-1-picoline _ activation.

The aminobenzamide of general formula VI can obtain by three route one of explanation in the following flow process 1, wherein Z, R ⁷, R ⁸The same with the Ar definition.Article one route comprise the commercially available anthranilic acid IV that makes suitable replacement and formula IX the direct coupling of amine (step I ii), it has more detailed explanation in following reference example 4A. the raw material amine of formula IX is by preparing below with reference to the explanation among the embodiment 1A.

The second route comprise the commercially available nitrobenzoic acid III coupling that makes suitable replacement, subsequently with nitroreduction for amino (step I and ii). these steps have more detailed explanation respectively in following reference example 2A and 3A.Article three, route comprised for four steps, was begun by commercially available amino ester VII.This route has more detailed explanation in following reference example 5.

Flow process 1

In method mutation (b), the amine of formula XX is that technology conventional in the compound known or the available organic chemistry is prepared by known raw material, and the explanation of for example press among the embodiment 3 prepares.The intermediate bromide of formula XII is handled with bromizating agent by corresponding formula XVII oxy-compound and is prepared. and suitable bromizating agent comprises N-bromosuccinimide. and formula XVII oxy-compound prepares by the explanation in the flow process 2. being reflected at of flow process 2 below with reference to more detailed explanation is arranged among the embodiment 7.

Flow process 2

Raw material formula XIII aminoderivative (wherein P is a hydroxyl protecting group) is by corresponding protected nitro-derivative was also prepared originally, as in EtOH, at PtO ₂Use H under existing ₂To handle and prepare. protected nitro-derivative gets by unprotected nitro-derivative is handled with the protecting group that group P is provided.

Step (i) is generally undertaken by formula XIII and XIV compound are reacted in the presence of alkali such as triethylamine.With the compound that obtains step (ii) in reduction, as reducing under the condition illustrated in above preparation compounds X III, obtain the midbody compound of formula XV.

Step (iii) is included in the organic solvent, in the presence of alkali, with formula XV compound compound R ⁹-COCl handles, and obtains formula XVI compound. will back one compound step (iv) in deprotection, with the formula XVII deprotection derivative that obtains with step (the bromizating agent processing v) obtains required formula XII compound.

Formula (Ia) compound can prepare by laxative remedy, and this method comprises:

(a ') is with the aminobenzamide of formula VIII '

R wherein ³¹And R ⁴¹Define the samely, if desired, can choose wantonly protectedly, Z ' is with the lower section

Wherein r, s, R ¹¹And R ²¹Define the samely, use formula R ⁵¹The carboxylic acid of-COOH or its activated derivatives are handled, wherein R ⁵¹Define the same; Or

(b ') is with formula XII ' compound:

R wherein ⁵¹Define the samely, use the amine of formula IX ' to handle:

Wherein r, s, R ¹¹And R ²¹Define the samely, production (Ia) compound is R wherein ³¹And R ⁴¹All be hydrogen; Or

(c ') is with the azalactones of formula XIII ':

R wherein ⁵¹Define the samely, handle with the amine of formula (IX ')

Wherein r, s, R ¹¹And R ²¹Define the samely, production (Ia) compound is R wherein ³¹And R ⁴¹All be hydrogen; And can slough the protecting group of any optional existence if desired; and/or if desired; a kind of formula (Ia) compound can be changed into another kind of formula (Ia) compound and/or; if desired; a kind of formula (Ia) compound can be changed into its pharmacy acceptable salt and/or; if desired, salt can be changed into free formula (Ia) compound.

In method mutation (a '), carboxylic acid R ⁵¹-COOH can commercially obtain or can be according to preparing below with reference to the explanation among the embodiment 6B. and this acid can be activated into corresponding acyl chlorides R ⁵¹It can or pass through-COCl. free carboxy acid R by the commerce acquisition ⁵¹-COOH handles and makes with thionyl chloride. perhaps, and carboxylic acid R ⁵¹-COOH can use cyclohexyl-N-(2-morpholino ethyl)-carbodiimide methyl-right-tosylate and I-hydroxybenzotriazole, or with iodate 2-chloro-1-picoline _ activation.

The 2-aminobenzamide of general formula VIII ' can prepare by two route one. and article one route comprises the reduction of corresponding 2-nitrobenzamide, as at PtO ₂Catalyzer exists uses hydrogen treat down. and this 2-nitrobenzamide can make by the 2-nitrobenzoic acid of corresponding optional activation is handled with the formula IX ' of the same definition again. and the preparation of the amine of formula IX ' is pressed below with reference to the explanation among the embodiment 1B. synthesize step explanation in following flow process 3 of VIII ' intermediate. the step in the flow process (i), illustrate in following reference example 2B, 3B and 4B respectively that (ii) and (iii) step (iii) illustrates in reference example 4B. the preparation of amine IX ' illustrates in reference example 1B.

Flow process 3

In method mutation (b '), formula XII ' intermediate is by the hydrolysis preparation with corresponding methyl ester, and the latter is by preparing commercially available methyl o-aminobenzoate in the presence of triethylamine, in methylene dichloride with the acyl chlorides processing.The explanation in of these steps below with reference to embodiment 6.

In method mutation (c '), the azalactones of formula XIII ' is by with commercially available anthranilic acid general formula R ⁵¹-COCl acyl chlorides was handled 3-8 hour under 0 ℃ in pyridine or pyridine/methylene dichloride mixed solution and is prepared.

By method commonly used, formula (I) compound can be changed into pharmacy acceptable salt, salt also can change into the free compound. and salt can be single-or two-salt. when in the structure of formula (1) compound two basic nitrogen atoms being arranged, can form two salt. suitable salt comprises and pharmaceutically acceptable inorganic or salt that organic acid forms. and representative examples of mineral pigments comprises hydrochloric acid, sulfuric acid and ortho-phosphoric acid. and the organic acid example comprises time-toluenesulphonic acids, methylsulfonic acid, glactaric acid and succsinic acid. and two salt are particularly including two-hydrochloride and two-mesylate.

By method commonly used, can with formula (I) compound optional change into other-kind of formula (I) compound.For example, can change into formula (I) compound that contains free hydroxyl group by hydrolysis such as alkaline hydrolysis with containing formula (I) compound of esterified hydroxy groups as-OCOMe. formula (I) compound that contains free hydroxyl group can be by esterification, as with suitable carboxylic acid, carboxylic acid halides or anhydride reaction, change into formula (I) compound that contains esterified hydroxy groups.

The compound that contains halogen can change into the compound that contains aryl by Suzuki coupling (Miyaura M, Yanagi T and Suzuki, A, Synth.Commun.1981, the 11st volume, the 513rd page). and formula (I) compound that contains nitro is by reduction, as at PtO ₂Catalyzer exists down uses hydrogen treat, can change into and contain amino formula (I) compound. and similarly, formula (I) compound that contains nitro is by reduction, as under the condition of suitably control, at PtO ₂Catalyzer exists down uses hydrogen treat, can change into formula (I) compound that contains hydroxylamino-NHOH.

Show that multiple drug-fast cancer cells is called as the MDR cell, it compares with corresponding drug sensitive cell, and drug accumulation demonstrates the reduction effect in the cell. as previously mentioned, show with the in vitro study of deutero-MDR clone: MDR generally is considered to many hydrophobic drugs are played a part the efflux pump with the relevant .P-gp of increase with medicine glycoprotein of plasmalemma (P-gp) expression in conjunction with character, the transfection research of carrying out with the P-gp that clones shows: its overexpression can give cell MDR phenotype: for example, see Ann.Rev.Biochem 58137-171 (1989).

The main effect of P-gp in healthy tissues is to export intracellular toxin from cell. and overexpression that evidence suggests P-gp can play clinical effect on the multiple resistance. and having detected P-gp mRNA or protein level in many kinds of human cancer-leukemia, lymphoma, sarcoma and cancers increases. really, found that in many cases the P-gp level increases in the tumour biological tissue that chemotherapy recurrence back obtains.

Shown that inhibition to P-gp effect among the MDR of P-gp mediation can cause accumulating only of cancer therapy drug in the cell. for example, shown verapamil, a kind of calcium channel blocker of knowing can reach the external MDR of making cell in vivo to the vinca alkaloids sensitivity: Cancer Res., 41,1967-1972 (1981). the mechanism of action of being inferred is for combining with P-gp with cancer therapy drug competition ground. illustrated-on a large scale the incoherent resistance conditioning agent of structure by this mechanism work as tamoxifen (tamoxifen: ICI) and relevant compound, reach cyclosporin A and derivative.

The anthranilic acid derivative of discoverable type I and pharmacy acceptable salt (being referred to as " The compounds of this invention " later on) thereof have the activity of P-gp inhibitor in biological test. available they regulate MDR, particularly this result of MDR. of P-gp mediation lists in following embodiment 1. as the P-gp inhibitor, The compounds of this invention can be used as multiple resistance conditioning agent, be also referred to as the resistance conditioning agent or the RMAs. The compounds of this invention can be regulated, as reduce or eliminate multiple resistance, the multiple resistance of P-gp mediation particularly.

Therefore, The compounds of this invention can be used on enhancing to have in the Cytotoxic method of Cytotoxic medicine tumour cell. and this method comprises, gives this tumour cell a compound of the present invention when cell toxicity medicament is a problem as being exposed to when tumour cell. therefore can increase the therapeutic action of chemotherapy or antineoplastic agent. the multiple resistance at chemotherapeutic period tumour cell pair cell cytotoxic drug can be lowered or eliminate.

The compounds of this invention also can be used on wherein, and the infective pathogen body demonstrates multiple resistance, especially in the method for the treatment of diseases of the multiple resistance form of the multiple resistance of P-gp mediation such as malaria (plasmodium pernicious malaria), tuberculosis, leishmaniasis and Entamoeba histolytica. this method comprises, as, give a compound of the present invention and pathogenic agent it is demonstrated multiple drug-fast medicine (administration respectively, administration simultaneously or order administration). therefore can strengthen the therapeutic action of medicine to multiple resistance pathogenic agent.

The available method that gives a kind of The compounds of this invention that comprises is treated the human or animal patient that the suffers from tumour resistance to chemotherapeutics. with The compounds of this invention with the effective dose administration to strengthen the cytotoxicity of this chemotherapeutics. the chemotherapy that proposes in the literary composition of the present invention or the example of antitumor drug comprise vinca alkaloids such as vincristin and vincaleucoblastine; Anthracycline microbiotic such as daunoblastin and Zorubicin; Mitoxantrone; Dactinomycin; Taxines (taxanes) is as taxol; Etoposide such as EPEG and Plicamycin (plicamycin).

The compounds of this invention also can be used on absorption, distribution, the metabolism that strengthens medicine and/or eliminates in the method for characteristic, this method comprises to the patient respectively, simultaneously or take a kind of The compounds of this invention and this medicine in order. this method is used in particular for strengthening medicine and enters central nervous system, or strengthens the oral absorption of medicine.

For example, The compounds of this invention can be used on medicine is easy in the method for the transhipment by hemato encephalic barrier, and is used for the treatment of AIDS or the relevant syndrome of AIDS. and need the human or animal patient of this treatment to treat by comprising the method that gives a kind of The compounds of this invention.

The compounds of this invention can be by various dosage form administrations, for example oral as with the form of tablet, liquor or the suspension of tablet, capsule, sweet tablet or film dressing, or parenterai administration such as intramuscular, vein or subcutaneous administration. so The compounds of this invention can be by injection or infusion administration.

Dosage is according to various factors, comprise patient's age, body weight and the state of an illness and route of administration. still, when usually the adult takes The compounds of this invention separately, the dosage that every kind of administration adopted is per kilogram of body weight 0.001-50mg, the most frequently used be 0.01-5mg. for example, can every day 1-5 time by a large amount of infusions, the mode of perfusion and/or repeat administration gives this dosage between several hours.

The anthranilic acid derivative of formula (I) or its pharmacy acceptable salt can be made and comprise pharmaceutically or the medicinal or veterinary composition of acceptable carrier or thinner on the veterinary drug. said composition is generally by method preparation commonly used, and can be pharmaceutically or suitable mode administration on the veterinary drug. so we provide and comprise the medicine of a kind of The compounds of this invention as multiple resistance conditioning agent.

The compounds of this invention can be following any usual way administration:

A) oral, as, tablet, coating tablet, dragee, lozenge, lozenge, water-based or oil-based suspension, liquor, dispersed powder or particle, emulsion, hard or soft capsule or syrup or elixir. the composition that orally uses can prepare according to the known any method of preparation medicinal compositions in this area, and this based composition can contain one or more reagent that are selected from sweeting agent, correctives, tinting material and sanitas so that medicinal attractive in appearance and good to eat preparation to be provided.

The mixture of the active ingredient that tablet comprises and the nontoxic pharmaceutically acceptable vehicle that is suitable for preparing tablet. these vehicle can be as, natural instincts thinner, for example lime carbonate, yellow soda ash, lactose, dextran, sucrose, Mierocrystalline cellulose, W-Gum, yam starch, calcium phosphate or sodium phosphate; Granulating agent or disintegrating agent, for example W-Gum, alginic acid, alginate or glycolic acid Starch Sodium; Tackiness agent, for example starch, gelatin or gum arabic; Lubricant, for example silicon-dioxide, Magnesium Stearate or calcium stearate, stearic acid or talcum powder; Effervescent mixture; Tinting material, sweeting agent, wetting agent such as Yelkin TTS, Spheron MD 30/70 or lauryl sulfate. tablet not dressing maybe can be by known technology coatings to delay in GI disintegration and absorption, retarding action is provided thus in a long time. for example can use a kind of time dilation material such as glyceryl monostearate or two glyceryl monostearates. these preparations can be with known method preparation, for example by mixing, granulation, compressing tablet, sweet tablet or film dressing process.

Oral preparations is hard capsule also, wherein described activeconstituents is mixed mutually with inert solid diluent such as lime carbonate, calcium phosphate or kaolin, or soft capsule, wherein said activeconstituents Individual existence or can mix existence with water or oil medium such as peanut oil, whiteruss or olive oil phase.

Aqueous suspension contains and is suitable for preparing the active substance of the mixed with excipients of liquid suspension. and these vehicle are suspensoid, for example Xylo-Mucine, methylcellulose gum, Vltra tears, sodiun alginate, polyvinylpyrrolidone, tragakanta and gum arabic; Dispersion agent or wetting agent can be the phosphatide that nature exists, for example the condensation product of the condensation product of Yelkin TTS or alkylene oxide and lipid acid such as polyoxyethylene stearic acid ester or oxyethane and long chain aliphatic alcohol such as heptadecyl vinyloxy group hexadecanol (heptadecaethyleneoxycetanol) or oxyethane and derived from the condensation product of the part ester of lipid acid and hexitol such as polyethylene sorbitan monooleate or oxyethane and derived from the condensation product such as the polyethylene polyoxyethylene-sorbitan mono-oleate of the part ester of lipid acid and hexitan.

This aqueous suspension also can contain one or more sanitass, for example ethyl p-hydroxybenzoate or n-propyl, one or more tinting materials, for example sucrose or asccharin.

Oil-based suspension can be by being suspended in vegetables oil with activeconstituents, for example peanut oil, sweet oil, sesame oil or Oleum Cocois, or be suspended in mineral oil such as the whiteruss and make. oil-based suspension can contain thickening material, as beeswax, paraffinum durum or hexadecanol.

For good to eat preparation is provided, can add as above sweeting agent of carrying or correctives. these compositions can be preserved by adding oxidation inhibitor such as xitix. are suitable for providing and dispersion agent or wetting agent, suspensoid and one or more sanitass blended activeconstituents mutually by adding dispersed powder that entry makes aqueous suspension and particle. suitable dispersion agent or wetting agent and suspensoid are mentioned explanation in the above. also there is other vehicle, as sweeting agent, correctives and tinting material.

Medicinal compositions of the present invention is emulsion oil-in-water form also. and oil phase can be vegetables oil such as sweet oil or peanut oil, or mineral oil such as whiteruss, or these oily mixtures. suitable emulsifying agent can be naturally occurring glue, as gum arabic or tragakanta, naturally occurring phosphatide, as soybean lecithin, reach ester or part ester derived from lipid acid and hexitan, as polyoxyethylene-sorbitan mono-oleate, and the condensation product of this part ester and oxyethane, as polyoxyethylene sorbitan monooleate. emulsion also can contain sweeting agent and correctives. and syrup and elixir can be used sweeting agent, as glycerine, sorbyl alcohol or sucrose are prepared. and particularly diabetic subject's syrup can contain the material that only is used for carrier, as sorbyl alcohol, it is not metabolized to glucose or only metabolism minute quantity is a glucose.

These formulations also can contain demulcen, sanitas, correctives and tinting material;

B) parenterai administration (or in subcutaneous or intravenously or intramuscular or the breastbone or pass through infusion techniques) is to carry out with the form of aseptic injection water-based or oil-based suspension. and this suspension can have the above-mentioned wetting agent and the suspensoid of suitable dissemination to make with those according to the technology of knowing. and this aseptic injection preparation can be aseptic injectable solution or the suspension that is dissolved in atoxic non-enteron aisle acceptable diluent or the solution, the solution in 1,3 butylene glycol for example.

Water, Ringer's solution and isotonic sodium chlorrde solution are arranged in used acceptable medium and the solvent.In addition, aseptic fixed oil commonly used is as solvent or suspension medium. and the fixed oil of any gentleness be can use for this reason, synthetic list or double glyceride comprised. lipid acid such as oleic acid can be used in the preparation of injection in addition.

C) inhalation is to carry out with the form of aerosol or spray solution.

D) rectal administration is to carry out with the form of suppository, this suppository is by forming medicine and suitable nonirritating mixed with excipients, being solid under this vehicle normal temperature but being liquid, therefore can melt and discharge medicine at the rectum place in rectal temperature. these materials are theobroma oil and polyoxyethylene glycol;

E) topical can liniment, the form of ointment, gel, eye wash, solution or suspension carries out.

Every day, dosage can change in a big way, to under each individual cases, adjust to meet independent needs. in a word, for adult's administration, the about 500mg of the about 5mg-of dosage range that every day is suitable, but can surpass this upper limit as if the situation is critical. every day dosage can single dose or divided dose give.

Further specify the present invention with following embodiment.

Embodiment 1: formula (I) compound and its salt are as the experiment of MDR conditioning agent Material and method

In 37 ℃, 5%CO ₂In, the subbreed AR1.0 of EMT6 mouse cell line of mammary gland and this MDR resistance is cultivated in containing RPMI 1640 substratum of 10% foetal calf serum and 2mM glutamine. (0.25% trypsinase behind the tryptic digestion, 0.2g/l, EDTA), cell is gone down to posterity between 1/200th and 1/2000th to parent clone, MDR resistance subbreed is gone down to posterity between 1/20th and 1/200th.

1. drug accumulation is measured

Measure preceding 48 hours, with AR1.0 cell inoculation (Canberra Packard) to the opaque culture plate in 96 holes. this mensuration substratum contains the mixed solution of tritiated daunoblastin (DNR) (0.3 μ Ci/Ml), cell toxicity medicament and unmarked DNR (2 μ M). formula (I) compound is become the concentration range of 0.508nM-10 μ M with the serial dilution of mensuration substratum. these cells were hatched under 37 ℃ 1 hour, active cell is measured in washing then. with the IC that accumulates ₅₀Come ecbatic, wherein 100% accumulates the observations that is meant in the presence of the RMA verapamil of known 100 μ M concentration.

The result is listing in the Table A down.

Table A

Compound number	IC 50(μ M) accumulates
		9591	0.425
9592	＞10
		9594	0.087
9595	0.37
		9596	0.132
9597	0.087
		9600	0.199
9606	＞10
		9608	0.224
9609	0.431
		9612	0.087
9613	0.098
		9614	0.278
9615	0.213
		9616	0.113
9617	0.203
		9621	0.453
9622	0.207
		9623	1.89
9625	0.347
		9626	0.278
9628	2.27
		9629	＞10
9630	0.235
		9631	0.669

9632	0.431
		9633	0.593
9634	6.955
		9635	0.669
9636	0.184
		9638	0.552
9639	0.108
		9640	0.194
9641	0.0019
		9642	0.341
9643	0.425
		9645	0.179
9646	0.295
		9647	0.033
9648	0.038
		9649	0.188
9650	0.061
		9651	0.071
9652	0.064
		9653	0.490
9654	0.135
		9655	0.557
9656	0.188
		9657	0.343
9658	2.90
		9659	1.38
9660	6.424

9661	0.362
		9663	0.175
9664	1.679
		9665	0.389
9666	8.672
		9667	0.076
9668	0.087
		9669	0.469
9677	0.169

9304	1.2
		9405	0.3
9354	0.6
		9350	0.8
9401	3.0
		9394	3.4
9349	0.3
		9398	1.5
9399	5.0
		9424	2.5
9420	1.9
		9435	1.9
9432	3.2
		9410	3.0
9256	1.7
		9297	0.4
9395	1.3

9331	1.3
		9294	0.4
9295	0.39
		9302	5.0
9310	1.2
		9334	1.3
9351	9.0
		9380	0.9
9381	3.0
		9426	0.69
9427	0.53
		9442	1.0
9459	0.65
		9460	1.0
9377	5.5
		9359	＞10
9384	＞10
		9391	＞10
9347	3.0
		9383	2.0
9385	1.2
		9389	1.8
9397	10
		9365	2.0
9367	1.0
		9531	0.035
9542	0.13

9543	0.07
		9554	0.99
9541	0.02
		9561	0.055
9562	0.024
		9564	0.2
9568	0.017
		9573	0.0095
9544	0.05
		9571	0.022
9574	0.019
		9576	0.064
9578	0.084
		9581	0.015
9584	0.36
		9588	0.094
9593	0.014
		9586	0.18
9589	1.0
		9545	0.8
9590	0.097
		9472	0.5
9482	0.54
		9483	1.7
9493	0.22
		9527	0.052
9557	0.012

9582	1.27
		9569	0.93
9456	0.3
		9510	0.71
9511	0.37
		9512	3.9
9489	0.15
		9500	0.19
9501	0.12
		9513	0.2
9514	0.25
		9494	0.4
9495	0.5
		9496	0.48
9497	1.6
		9503	2.0
9504	0.26
		9477	0.41
9517	0.4
		9518	0.3
9535	0.45
		9549	4.3
9559	2.06
		9534	0.14
9540	1.2
		9548	4.9
9523	1.6

9524	1.0
		9556	0.86
9447	0.7
		9461	1.8
9470	1.3
		9476	0.35
9536	0.45
		9538	0.22
9471	0.2
		9492	1.0
9526	1.4
		9515	1.2
9539	0.22
		9466	1.4
9479	2.1
		9567	0.16
9572	0.053
		9577	0.32
9585	0.04

2. the toxic enhancing of Zorubicin

(a) detect selected formula I compound and in the AR1.0 cell, strengthen the toxic ability of Zorubicin. in initial proliferation assay, with compound to separately to Zorubicin (the 0.34 μ m) tritiate of the nontoxic fixed concentration of AR1.0 cell. after Zorubicin is hatched four, with sulphur cyanamide B (sulphorhodamine) experiment (Skehan etc. of colorimetric; J Natl.CancerInst.82 1107-1112 page or leaf (1990)) measure propagation. the results are shown in Table B.

(b) Zorubicin (0.263nM-17.24 μ M) of cell and tritiate was cultivated four in the presence of certain density each compound. the explanation of Skehen etc. is carried out quantitatively propagation in by above-mentioned quoted passage. obtain Zorubicin itself and with the IC of each compound ₅₀(propagation of untreated contrast is reduced by 50% needed concentration), and be used for calculating enhancing index (PI):

The results are shown in Table C1 and C2.

Table B

Compound number	Toxicity of compound (IC 50μM)	Toxicity (IC with cell toxicity medicament 50μM)
			9304	8.0	0.15
9405	22	0.09
			9354	8.0	0.15
9394	10	0.1
			9349	5.5	0.14
9424	39	2.6
			9420	7.0	0.4
9435	9.0	0.4
			9432	35	0.2
9256	40	0.3
			9297	18	0.33
9395	9.0	0.15
			9331	7.0	0.04
9295	40	0.6
			9310	22	0.24
9334	8.0	0.05
			9351	43	1.3
9380	40	0.5

9381	50	1.5
			9426	7.0	0.06
9427	10	0.10
			9442	7.2	0.05
9459	8.5	0.09
			9460	7.5	0.18
9347	35	0.6
			9383	40	1.0
9385	40	0.55
			9389	30	0.3
9365	42	0.8
			9367	15	0.5
9531	1.1	0.005
			9542	1.9	0.014
9543	0.9	0.008
			9554	3.0	0.05
9541	0.86	0.006
			9561	13	0.01
9562	1.7	0.0028
			9564	0.4	0.008
9568	2.8	0.0034
			9573	4.0	0.0004
9544	1.9	0.0077
			9571	2.0	0.0008
9574	0.32	0.005
			9576	0.93	0.0018
9578	0.9	0.0014

9581	0.31	0.0038
			9584	8.6	0.015
9588	6.7	0.005
			9593	7.0	0.005
9586	7.4	0.04
			9589	36.8	4.4
9545	1.7	0.07
			9590	9.5	0.05
9472	6.5	0.12
			9482	12	0.22
9483	8.5	0.35
			9493	9.0	0.05
9527	4.5	0.007
			9557	9.0	0.02
9569	0.19	0.008
			9456	5.0	0.03
9510	2.8	0.05
			9511	4.0	0.06
9489	7.0	0.05
			9500	5.0	0.009
9501	3.0	0.04
			9514	7.0	0.07
9494	9.0	0.05
			9495	4.0	0.04
9496	4.0	0.03
			9497	9.0	0.08
9503	3.5	0.09

9504	5.0	0.06
			9477	4.0	0.04
9517	2.0	0.05
			9518	1.5	0.019
9535	2.6	0.015
			9549	5.6	0.52
9534	6.6	0.0002
			9540	6.2	1.0
9548	1.8	1.0
			9447	6.8	0.065
9461	7.5	0.3
			9470	3.5	0.075
9476	2.0	0.02
			9536	2.65	0.015
9538	2.3	0.014
			9471	2.6	0.02
9492	3.0	0.02
			9539	1.7	0.011
9466	6.0	0.05
			9567	1.7	0.028
9572	1.7	0.014
			9577	7.7	0.00035
9585	9.2	0.022

Table C1

	Enhancing index under RMA concentration
						Compound number	100nM	50nM	30nM	20nM	10nM

9594	601	307	159		11
						9595	45	2.99	1.93		1.45
9596	354	131	44		2.68
						9597	878	551	382		80
9600	2.55	1.98
						9608	178	118	60	31	6.7
9609	68	19	7.4	3.4	1.4
						9612	171	149	95		11
9613	168	97	35		3
						9614	52	32	9		2
9615	175	85	23		2
						9616	185	143	142		13
9617	81	15	4		1.5
						9621	25	4.4	1.6	1.3	1.0
9622	79	46	15	8	1.8
						9625	60	7	4		1
9626	27	8	4		1.2
						9630	26	6	2		1
9631	67	20	9		1
						9632	8	2.7	2.1		1.1
9633	13.7	3.4	1.3		1.0
						9635	7	2	1.3
9636	131	46	22		2.6
						9638	2.6	1.5	1.1
9639	136	78	34		2.6
						9640	23.8	4.6	2.5		1
9641	162	46	17		1.5

9642	14	2.5	1.2		1.0
						9643	6.7	2.4	1.5		1.0
9645	7.2	2.1	1.3		1.0
						9646	4.8	1.3	1.1		1.0
9647	6	1
						9648			34		16
9649	66	60	46		53
						9650	33	14	3		3
9651	2.2	1.1
						9652	7.6	1.8	1.2
9655	65	37	13		1.8
						9660	1.4	1.2	1.1
9661	195	71	38		1.2
						9663	82	74	80		50
9664	116	37	1.9		1
						9665	50	28	7		1.4
9667
						9668
9669
						9677

Table C2

Compound number	Enhancing index under RMA concentration
						500nM	300nM	100nM	30nM	10nM
	9304	30
9405						8.6

9354	20
						9394	12
9349	22
						9424	37
9420	25
						9297		16
9395	21
						9331	120	40
9294	71	18
						9295		16
9426	65
						9427	32	14
9442	67	27
						9459	112	45
9460	36	18
						9531		160	150	120	30
9542		160	128
						9543		150	150	120	24
9554			90
						9541		160	160	150	75
9561			100	60	14
						9562			83	60	40
9564			129
						9568			88	60	23
9573			100	94	83
						9544		150	120	67	15
9571			100	100	38

9574			94	60	16
						9576			280	225	78
9578				188	43
						9581				300	90
9584				36	2.1
						9588				68	6
9593				57	6
						9586				6	5
9589				1	1
						9590				14	2
9483	24	14
						9493	200	85	7.6
9527	120	103	50	11	1.5
						9557			100		1.2
9456		112
						9510	267	120	12
9511	214	120	12
						9489	303	192	77
9500		300	97	5.5
						9501		183	69	1.9
9514	120	40
						9494	148	38
9495	567	261	15	1.3
						9496	825	254	19	1.6
9497	200	52
						9503	77	36
9504	267	150	34

9477	63	29
						9417	120	40
9518	240	120
						9535		128	32
9447	340	40
						9461	30	13
9470	90	26
						9476	136	83
9536		128	32
						9538		128	43
9471	230	115
						9539		128	32
9466	60	30
						9567			112	8	1.7
9572			83	25	2.7
						9577			112	18	2.2
9585				7.2	1.3

3. The toxic enhancing of various cell toxicity medicaments

Described flow process is measured the enhancing index of the selected compounds that uses various clones and the various cell toxicity medicaments except that Zorubicin when measuring according to above Zorubicin, the results are shown in Table D.

Table D

			Enhancing index under RMA concentration
						Compound number	Clone	Cell toxicity medicament	50nM	30nM	10nM
9594	2780AD	Taxol	1126	425	18
						9594	H69/LX4	Vincristin	356	79	2

9594	AR1.0	Taxol	407	308	50
						9596	2780AD	Taxol	743	160	3.5
9596	H69/LX4	Vincristin	158	2	1
						9597	2780AD	Taxol	2070	1427	110
9597	H69/LX4	Vincristin	44	41	1
						9608	H69/LX4	Taxol	130	17	1.6
9609	H69/LX4	Taxol	9	3	1
						9612	H69/LX4	Taxol	1329	894	51
9613	H69/LX4	Taxol	877	236	2.2
						9614	H69/LX	Taxol	11	1.1
9576	AR1.0	Etoposide	51	45	26

Reference example 1A: the preparation of general formula I X amine

Preparation shown in the general formula I X amine according to the form below 1

Table 1

Method IX.b

Undertaken 3 by method 2b is (iv) described, the reductive amination process of 4-dimethoxy benzaldehyde, obtain intermediate secondary amine. perhaps, this amine can prepare with the lithium aluminium hydride reduction carbamate by making the reaction of veratrylamine and methyl-chloroformate again. acetonitrile (25ml) mixed solution of this amine (3.76g), 4-p-ethyl bromide (4.78g) and yellow soda ash (3.3g) is heated to backflow 3 hours.After the cooling, the aqueous solution is handled and is obtained orange (1.75g).In ethanol, under the hydrogen, nitro is obtained amine IX.b (1.3g) through the reduction of platinum dioxide (IV) catalyst.

Method IX.c

Under room temperature, with the 4-nitro thiophenol (1.00g, 6.44mmol), acetonitrile (15ml) mixed solution of glycol dibromide (1.39ml, 2.5 equivalents) and salt of wormwood (2.22g, 2.5 equivalents) stirred 30 minutes.The aqueous solution is handled and fractional crystallization gets bromide intermediate (0.8g, 47%).

With this bromide (336mg, 1.28mmol), 6,7-dimethoxy-1,2,3, and the 4-four hydrogen isoquinoline hydrochloric acid salt (294mg, 1.28mmol) and salt of wormwood (372mg, 2.1 being heated in acetonitrile (10ml), mixture equivalent) refluxed 3 hours. the aqueous solution is handled and flash chromatography (ethyl acetate/hexane) obtains required tertiary amine (236mg, 49%).

With concentrated hydrochloric acid (0.3ml) join this tertiary amine (236mg in methyl alcohol 0.63mmol) (2ml) suspension, adds iron (151mg), with reaction mixture be heated to 80 ℃ 2 hours. the aqueous solution is handled the amine IX.c (195mg, 90%) that obtains to jelly.

Method IX.d

By with IX.cSimilarly method is made feedstock production with p-NP.

In ethanol, under the hydrogen, carry out the reduction reaction of nitro with platinum dioxide (IV) catalyzer.

Method IX.e

With yellow soda ash (611mg, 5.76mmol) join the 1-methyl-6 of stirring, 7-dihydroxyl-1,2,3,4-tetrahydroisoquinoline hydrobromate (1.0g, 3.84mmol) acetone-water (25ml, 4: 1) in the solution. mixed solution is cooled to 0 ℃, add then chloroformic acid benzyl ester (0.63ml, 4.19mmol). make mixed solution rise to room temperature, stirred 2 days. reaction mixture is filtered, separates, vacuum concentrated filtrate. the aqueous solution that obtains is poured among the EtOAc (80ml), with the organic phase water (3 * 40ml), salt solution (40ml) washing, dry (MgSO ₄), vacuum concentration gets brown oil again. through flash chromatography (SiO ₂Hexane: EtOAc, 1: 1) purifying gets white foam shape benzyl carbamate (817mg).

With sodium hydride (60% dispersion liquid; 2.10g, 0.05mol) and methyl iodide (27.25ml, (2.74g is in THF 8.75mmol) (100ml) solution 0.44mol) to join this benzyl carbamate.Add DMSO (50ml) then, with reaction mixture in the heated overnight down that refluxes. reaction mixture is poured in EtOAc (200ml) and the water (100ml). extract organic phase, water (3 * 100ml), salt solution (100ml) washing, drying (MgSO ₄) must brown oil. through flash chromatography (SiO ₂Hexane: EtOAc, 2: 1) purifying, get yellow crystal solid dimethoxy intermediate (2.7g).

By (2.7g 8.63mmol) is dissolved in MeOH/CH with this intermediate ₂Cl ₂(1: 1,270ml) in, under atmospheric pressure reduced 4 days with Pd/ gac (700mg), under 40p.s.i pressure, continue reduction again and came cracking benzyl carbamate group in 12 hours. filter, vacuum concentration obtains the crude product secondary amine (1.89g) of orange.

Make the reaction of this amine and 4-p-ethyl bromide then, and obtain the amine IX.e. of orange solids by method IX.b reduction

Method IX.f

In acetonitrile (20ml), with 4-oil of mirbane ethylamine hydrochloride (770mg, 3.8mmol), α, α '-two bromo-o-Xylol (1.00g, 3.8mmol) and salt of wormwood (1.83g, 13.3mmol) reflux 2 hours. the aqueous solution is handled, and flash chromatography (dichloromethane solution of 5% methyl alcohol) obtains required tertiary amine (297mg, 29%).

In the ethanol/methylene mixed solution, with nitroreduction, use flash chromatography (ethyl acetate/hexane) purifying to obtain amine IX.f (187mg, 71%) again with platinum dioxide (IV) catalyzer normal pressure hydrogenation.

Method IX.g

Under 0 ℃, with 3-oil of mirbane ethanol (2.11g), methylsulfonyl chloride (2.44ml, 2.5 equivalent) and the methylene dichloride mixed solution of triethylamine (1.76ml, 2 equivalents) stirred 4.5 hours. the aqueous solution is handled requiredly is the methanesulfonates of yellow solid (2.27g, 73%).

N at this methanesulfonates (2.27g), add 6 in dinethylformamide (20ml) solution, 7-dimethoxy-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt (2.13g, 1 equivalent) and salt of wormwood (3.2g, 2.5 equivalent), reaction mixture is heated to 100 ℃ 4 hours. the aqueous solution handle the tertiary amine (1.49g, 47%) of yellow oil.

In ethanol and methylene dichloride, with platinum dioxide (IV) catalyzer, under hydrogen, carry out the reduction reaction of nitro, obtain IX.g (1.11g).

Method IX.h

At N, in the dinethylformamide, under the room temperature, with 4-nitrophenols (10g, 72mmol), Epicholorohydrin (11.2ml, 144mmol) and salt of wormwood (10g, 72mmol) mixture stirred 18 hours. the aqueous solution is handled the epoxy derivative (10.8g, 77%) that obtains canescence crystalline solid.

Under room temperature, with this epoxy derivative (1.09g, 5.6mmol), 6,7-dimethoxy-1,2,3,4-four hydrogen isoquinoline hydrochloric acid salt (2.1g, 9.3mmol) and salt of wormwood (1.3g, 9.3mmol) mixture in tetrahydrofuran (THF) (20ml) and water (5ml) stirred 72 hours. the aqueous solution is handled, and flash chromatography (ethyl acetate) purifying obtains the required alcohol of the white solid (390mg that is, 50%). carry out the hydrogenation of nitro by the explanation of method IX.b, obtain amine IX.h.

Method IX.i

In refluxing down, with 3-methyl-4-nitrobenzoic acid (5.0g, 0.03mol) and toluene (100ml) solution of thionyl chloride (10ml) heating 3 hours, put cold spending the night then. reaction mixture is concentrated, obtain acyl chlorides (quantitatively) with toluene and hexane azeotropic then, be canescence, low-melting solid. (press Vogel ' s Practical Organic Chemistry, the 4th edition at diazomethane, the 293rd page is described, usefulness excessive N-methyl-N-nitrosotoluene-to the sulphonamide preparation) the middle NEt that adds ₃(4ml). with reaction mixture cooling (ice bath), slowly add the Et of this acyl chlorides then ₂O liquid adds acetate until there not being N again after .2 hour ₂Gas is emitted. and filter mixed solution, vacuum concentration is dissolved in Et with residue ₂Among the O, washing (saturated NH ₄Cl, K ₂CO ₃The aqueous solution, salt solution), dry (Na ₂SO ₄), be concentrated into and crystallization occurs. place crystallization in the refrigerator, filter then and obtain diazo-ketones (2.03g), be the light brown solid.

In refluxing down, (2.0g, the heating of EtOH 10.0mmol) (13mmol) solution obtains brown solution, slowly adds silver benzoate (125mg, NEt 0.54mmol) with this diazo-ketones ₃(2ml) solution. mixed solution blackening, N ₂Gas is emitted. and addend part silver benzoate is not emitted to there being gas again, continues to reflux 55 minutes. and by diatomite filtration, vacuum concentration obtains brown solid again with reaction mixture. through flash chromatography (SiO ₂5% hexane-ethyl acetate) purifying obtains required ethyl ester (1.46g), is yellow solid. with this ethyl ester (1.35g 6.05mmol) is dissolved in 1, in 4-two _ alkane (50ml), adds entry (20ml) to muddy. add LiOH.H ₂O (762mg 0.017mol), under the room temperature spends the night the mixture stirring. and regulate mixed solution to acid with hydrochloric acid, extract CH ₂Cl ₂(in 3 * 80ml), dry (MgSO ₄), vacuum concentration obtains required acid (633mg), is orange solids.

Under the room temperature, should acid (630mg, 8.23mmol) and I-hydroxybenzotriazole hydrate (546mg, 4.04mmol) DMF (30ml) mixed solution stirring 10 minutes. add 6,7-dimethoxy-1,2,3, and the 4-tetrahydroisoquinoline (780mg, 4.04mmol), add dicyclohexylcarbodiimide (667mg again, 3.23mmol), the mixed solution stirring is spent the night. the filtering reaction mixed solution, with the filtrate vacuum concentration, use dilute hydrochloric acid earlier, handle with diluted sodium hydroxide solution again, be extracted into CH ₂Cl ₂In. with organic phase washing (using salt solution after the first water), dry (Na ₂SO ₄). vacuum steam desolventize yellow residue. through flash chromatography (SiO ₂Hexane: ethyl acetate, 1: 1) purifying obtains required acid amides (760mg), is canescence crystalline solid. the conditions of similarity described in the usefulness method IX.b, and use Pd/ gac (50mg) with nitroreduction. through flash chromatography (SiO ₂Hexane: ethyl acetate, 1: 1) purifying obtains intermediate amine (695mg), be white foam shape thing. by under room temperature with this acid amides (730mg, 2.15mmol) tetrahydrofuran (THF) (10ml) solution join the lithium aluminum hydride (244mg of stirring, 6.43mmol) the suspension of THF (5ml) in and with this reduction of amide. reaction mixture was refluxed 2 hours again, cool off, carefully add the CH of entry (0.5ml) then ₂Cl ₂(20ml) liquid. add MgSO ₄, reaction mixture was stirred 10 minutes, to filter, vacuum-evaporation filtrate obtains required amine IX.i (661mg), is canescence crystalline solid.

Method IX.j

Make raw material with 3-methoxyl group-4-nitrobenzoic acid, use with the similar method of IX.i to prepare amine IX.j.

Method IX.k

Under room temperature, with this amine (336mg, 1.61mmol), 4-nitrobenzyl bromine (289mg, 1.34mmol) and salt of wormwood (277mg, 2.01mmol) acetonitrile (50ml) mixed solution stirred 2.5 hours. the aqueous solution is handled and is obtained required intermediate, by method IX.b nitroreduction is obtained IX.k again, is yellow oily liquid (380mg).

Method TX.l

With 2-(4-nitrophenyl) propionic acid (5.0g, 26mmol) and thionyl chloride (3.75g, 52mmol) mixture heating up in toluene (30ml) is to refluxing 2 hours, cooling, solvent removed in vacuo obtains acyl chlorides. under 0 ℃ with this acyl chlorides (5.47g, 26mmol) be dissolved in the methylene dichloride (50ml), in this solution, add 6,7-dimethoxy-1,2,3, and the 4-tetrahydroisoquinoline (3.7g, 24mmol) and triethylamine (5.4ml, 39mmol), stirring reaction mixed solution 7 hours. acid/alkaline purification, flash chromatography (dichloromethane solution of 1% methyl alcohol) obtains required acid amides (4.98g, 56%).

Nitro with hydrogenation under the palladium charcoal normal pressure, in tetrahydrofuran (THF), is become required amine IX.l. with lithium aluminum hydride with this reduction of amide

Method IX.m

With butyl iodide with the isovanillin alkylation, obtain intermediate secondary amine by the (iv) described reduction amination that carries out of method 2b then. this amine and 4-p-ethyl bromide are reacted in acetonitrile, use platinum dioxide (IV) catalyzer in the hydrogen under the normal pressure, nitro hydrogenation to be obtained required amine IX.m. then

Method IX.n

By method IX.g, prepare methanesulfonates with the 3-p-ethyl bromide. under 90 ℃, with this methanesulfonates (1.0g, 4.1mmol) and sodium cyanide (400mg, 8.2mmol) mixture in methyl-sulphoxide (25ml), stirred 7 days. the nitrile (651mg that the aqueous solution is handled requiredly, 91%). this nitrile (651mg) is heated to backflow 5 hours in 1.5M sodium hydroxide solution (25ml). the aqueous solution is handled and is obtained intermediate carboxylic acid (548mg). and the toluene liquid with thionyl chloride converts it into acyl chlorides, again with 6,7-dimethoxy-1,2,3, the reaction of 4-tetrahydroisoquinoline generates acid amides. and use then with the similar method of method IX.i acid amides and nitroreduction are obtained amine IX.n.

Method IX.o

With 3,4-dimethoxy-benzoyl chloride (3.9g, 19.2mmol) and 7-nitro-1,2,3,4-tetrahydroisoquinoline (2.81g, 15.8mmol) methylene dichloride (200ml) mixed solution stirred 2 hours, filter then. collect filtrate, behind aqueous solution processing and the flash chromatography (dichloromethane solution of 1-10% methyl alcohol), obtain required acid amides (3.25g, 46%), be yellow oil. use similar method then, with acid amides and nitroreduction with method IX.i. obtain amine IX.o (1.37g) into yellow oil.

Method IX.p

In methyl alcohol, with 4-oil of mirbane ethylamine hydrochloride and 3, the 4-dimethoxy benzaldehyde stirred 3 hours with triethylamine. add hexane then, be settled out required imines, filter to collect. this imines is reduced into secondary amine with the methanol solution of sodium borohydride, then the acetonitrile liquid reflux of this amine and 2-iodopropane and salt of wormwood being come alkylation in 16 hours. usefulness palladium charcoal with nitro hydrogenation, obtains amine IX.p in hydrogen, be yellow jelly.

Reference example 1B: the preparation of general formula I X ' amine

Preparation shown in general formula I X ' the amine according to the form below 3.

Table 3

The preparation of 3-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-propylamine (IX ' d)

In 100 ℃, with 6,7-dimethoxy-1,2,3, the 4-four hydrogen isoquinoline hydrochloric acid salt (5g, 20mmol), the 3-chloroethyl nitrile (1.96g, 20mmol) and salt of wormwood (9g, DMF 60mmol) (100ml) mixed solution heating 4 hours. vacuum concentration, handle, concentrate and obtain the intermediate nitrile, be light yellow solid (3.68g).

Under 0 ℃, nitrogen, at this intermediate nitrile (600mg, 2.44mmol) tetrahydrofuran (THF) (5ml) solution in add lithium aluminum hydride (280mg, 7.32mmol) tetrahydrofuran (THF) (25ml) suspension. reactant was stirred 30 minutes, temperature was to room temperature 12 hours again. slowly add entry (0.28ml), NaOH (2N, 0.28ml) and water (0.9ml) termination reaction. with the mixed solution dried over mgso, filter.The vacuum concentration organic layer obtains title compound IX ' .d, is yellow oil (510mg).

Reference example 2A: the preparation of the 2-nitrobenzamide of general formula V

With 4,5-dimethoxy-2-nitrobenzoic acid (7.0g, 0.031mol) and the mixture of thionyl chloride (4.5ml, 2 equivalents) in toluene (140ml), be heated to and refluxed 2 hours. after the cooling, vacuum is removed solution, obtains the acyl chlorides (quantitative yield) into yellow solid,

Under room temperature, methylene dichloride (18ml) mixed solution of acyl chlorides (851mg), amine IX.m (1.09g) and triethylamine (1 equivalent) was stirred 18 hours.The aqueous solution is handled, and flash chromatography (ethyl acetate) obtains required 2-nitrobenzamide V.13 (737mg), is white solid.

According to similar synthetic route, use the nitrobenzoic acid or nitrobenzoyl chloride and the amine IX that suitably replace, listed formula V nitro-compound in the preparation following table 4.

Table 4

In above each flow change method, can be by with suitable nucleophilic reagent such as amine or mercaptan, at appropriate solvent N, in dinethylformamide or the acetonitrile, carry out halogenide and exchange 2-nitro-5-halobenzamides as V.16 or V.26 changing into another kind of formula V compound.V.18

To (200mg V.16,0.42mmol) N, add sulfo-sodium methylate (50mg in dinethylformamide (2ml) solution, 0.72mmol), under the room temperature reaction mixture was stirred 72 hours. then mixed solution is diluted with ethyl acetate, use the salt water washing, through dried over mgso, V.18 solvent removed in vacuo obtains, and is yellow solid (190mg, 89%).

By acetonitrile mixed solution V.26 is heated to backflow 8 hours with excessive dimethylamine (40% the aqueous solution), can prepare nitrobenzamide V.17.

Reference example 2B: the preparation of the 2-nitrobenzamide of general formula VI '

N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-phenyl }-2-nitro-4-trifluoromethyl-benzamide (VI ' .24)

In refluxing down, with 2-nitro-α, α, α-trifluoromethyl-paratolunitrile (0.25g, 1.06mmol), the mixed solution heating of thionyl chloride (0.5ml) and toluene (5.0ml) 4 hours. vacuum concentrated solution, obtain the crude product acyl chlorides with methylbenzene azeotropic. with its be added to amine IX ' .b (0.28g, 0.88mmol) and triethylamine (0.18ml, anhydrous CH 1.33mmol) ₂Cl ₂(10ml) in the solution, stirring at room 24 hours. after the processing, obtain compound VI ' 24 (0.44g), be pale powder with the ether grinding.

According to similar synthetic route, use suitable nitrobenzoic acid V ' and amine IX ', listed formula VI ' nitro-compound in the preparation following table 5.

Table 5

Reference example 3A: the 2-aminobenzamide for preparing general formula VI by corresponding nitro-compound

Will be V.12 (140mg, ethanol 0.30mmol) (5ml) and CH ₂Cl ₂(5ml) solution feeds nitrogen, and the platinum oxide (IV) of adding pulpous state is (30mg). and mix liquid 2 hours under the normal pressure hydrogen, pass through Celite ^TMFilter, vacuum concentration obtains VI.12 (126mg, 96%), is white foam shape thing.

By similar method, listed aminobenzamide VI. in the preparation table 6

Table 6

Nitro-compound V	2-aminobenzamide VI
		V.1	VI.1
V.2	VI.2
		V.4	VI.4
V.5	VI.5
		V.6	VI.6
V.7	VI.7
		V.8	VI.8
V.9	VI.9

V.10	VI.10
		V.11	VI.11
V.13	VI.13
		V.14	VI.14
V.15	VI.15
		V.17	VI.17
V.28	VI.28

The compound of the synthetic sulfur atom-containing of available in addition following method.

(140 μ L) joins V.3 (147mg of nitrobenzamide with concentrated hydrochloric acid, 0.30mmol) methyl alcohol (2ml) solution in. add iron (72mg), with reaction mixture be heated to 80 ℃ 2 hours, cooling then. with reaction mixture alkalization (using saturated sodium carbonate solution), ethyl acetate extraction, dried over mgso, solvent removed in vacuo gets pale solid, obtain required 2-aminobenzamide through flash chromatography (ethyl acetate) purifying, VI.3 (47mg, 34%).

By similar approach, the 2-aminobenzamide that preparation is following.

Reference example 3B: the 2-aminobenzoyl for preparing general formula VIII ' by corresponding nitro-compound Amine

2-amino-N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-phenyl }-benzamide (VIII ' .23)

At VI ' .23 (12g, ethanol 0.026mol) (200ml) and CH ₂Cl ₂Feed nitrogen in the solution (160ml), add pulpous state platinum oxide (IV) (240mg).Mixed solution was stirred 4 hours under non-pressurized hydrogen, pass through Celite ^TMFilter vacuum concentration. obtain the white crystals (9.6g) of VIII ' .23 with recrystallizing methanol.

By similar method, listed aminobenzamide VIII ' in the preparation table 7.

Table 7

Reference example 4A: the 2-aminobenzoyl for preparing general formula VI by corresponding anthranilic acid Amine

VI.19

Under room temperature, with the amino pyrazine of 3--2-formic acid (500mg, 3.60mmol), amine IX.a (1.12g, 3.60mmol), N-cyclohexyl-N-(2-morpholino ethyl)-carbodiimide methyl-right-tosylate (1.68g, 3.96mmol), I-hydroxybenzotriazole (486mg, 3.60mmol) and triethylamine (501 μ L, anhydrous CH 3.60mmol) ₂Cl ₂(30ml) solution stirring is 5 days.The aqueous solution is handled and with after the re-crystallizing in ethyl acetate, is obtained title compound VI.19 (733mg), is faint yellow solid.

By above-mentioned similar method, listed aminobenzamide in the preparation table 8.

Table 8

Reference example 4B: the 2-aminobenzoic for preparing general formula VIII ' by corresponding anthranilic acid Acid amides

2-amino-N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-phenyl }-5-methyl-benzamide (VIII ' .12)

Under room temperature, 2-amino-5-tolyl acid (190mg, 0.96mmol), amine IX ' .b (300mg, 0.96mmol), N-cyclohexyl-N-(2-morpholino ethyl)-carbodiimide methyl-right-tosylate (449mg, 1.06mmol) and I-hydroxybenzotriazole (143mg, anhydrous CH 1.06mmol) ₂Cl ₂(10ml) solution stirring is 48 hours.The aqueous solution is handled and silica gel (is used methyl alcohol: ethyl acetate (2: 98) wash-out) behind the flash chromatography, obtain title compound VIII ' .12 (58mg), be faint yellow solid.

2-amino-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-4-fluoro-benzamide (VIII ' .07)

N-cyclohexyl-N-(2-morpholino the ethyl)-carbodiimide methyl-right-tosylate that stirs (238mg, 0.56mmol) and I-hydroxybenzotriazole (76mg, anhydrous CH 0.56mmol) ₂Cl ₂(10ml) add in the solution 2-amino-4-fluorobenzoic acid (80mg, 0.52mmol) add again triethylamine (0.08ml, 0.57mmol) and amine IX ' .a (200mg, 0.51mmol).Under room temperature, mixed solution was stirred 48 hours.After the processing, through silica gel (use methyl alcohol: rapid column chromatography ethylene dichloride (5: 95) wash-out), obtain aminobenzamide VIII ' .07 (57mg), be yellow solid.

By above two described similar approach, listed aminobenzamide in the preparation table 9.

Table 9

Reference example 5: the 2-amino amides for preparing general formula VI by corresponding 2-amino ester VII

VI.20

At 3-amino-2-thiophenecarboxylate (7.56g, 48.1mmol) methylene dichloride (40ml) solution in add two dimethyl dicarbonate butyl ester (11.55g, methylene dichloride 52mmol) (10ml) solution, add 4-Dimethylamino pyridine (600mg again, 4.8mmol). stirring at room is after 4 hours, reaction mixture is diluted with methylene dichloride, wash with water, use dried over mgso, solvent removed in vacuo obtains jelly, through flash chromatography (the hexane liquid of 10% ethyl acetate) purifying, obtain required t-butyl carbamate (4.40g, 36%).

(1.01g adds sodium hydroxide (316mg, water 7.9mmol) (4ml) solution in tetrahydrofuran (THF) 3.95mmol) (4ml) and methyl alcohol (8ml) solution at this t-butyl carbamate.After the stirring at room 18 hours, reaction mixture is acidified to pH4, ethyl acetate extraction is used dried over mgso, and solvent removed in vacuo obtains required acid, is white solid (800mg, 83%).

In room temperature, with this carboxylic acid intermediate (150mg, 0.62mmol), N-cyclohexyl-N-(2-morpholino ethyl)-carbodiimide methyl-right-tosylate (288mg, 0.68mmol), I-hydroxybenzotriazole (92mg, 0.68mmol) and IX.a (175mg, anhydrous CH 0.56mmol) ₂Cl ₂(8ml) solution stirring is 3 days.Then reaction mixture is diluted with methylene dichloride, dried over mgso is used in water and saturated sodium carbonate solution washing, solvent removed in vacuo obtains yellow jelly, through flash chromatography (silica gel, ethyl acetate) purifying, obtain required acid amides, be white foam shape thing (112mg, 33%).

With dry hydrogen chloride gas feed this acid amides (202mg, 0.38mmol) 1, in 4-two _ alkane suspension 10 seconds, reaction mixture was stirred 1 hour.With reaction mixture alkalization (yellow soda ash), ethyl acetate extraction is used dried over mgso then, and solvent removed in vacuo obtains amino amides, and VI.20 (151mg, 91%) is white solid.

By the following amino amides of similar approach preparation.

Table 10

Reference example 6A: the general formula R that can get on the non-commercial ⁹-CO ₂The preparation of H acid

(500mg is in the hot solution of trimethyl carbinol 2.61mmol) (7ml) and water (12ml), with 15 minutes dropping potassium permanganate (580mg, water 3.67mmol) (15ml) solution at 2-chloro-3-quinoline aldehyde.After stirring 1 hour down in refluxing, reaction mixture is put cold, filtering MnO ₂Precipitation, water and propyl carbinol washing.Regulate the pH to 5 of filtrate with the 2N hydrochloric acid soln, use chloroform extraction then, dried over mgso, solvent removed in vacuo obtains this acid (210mg, 39%) into yellow solid.

In addition, as 1, in 4-two _ alkane or the methyl alcohol, can obtain required acid in appropriate solvent by using sodium hydroxide or lithium that corresponding ester such as 2-methyl-thiazole-4-ethyl formate or 4-hydroxyl-quinoline-3-ethyl formate are hydrolyzed.

Reference example 6B: general formula R ⁵¹-CO ₂The preparation of H acid

(i) 4-cyclohexyloxy phenylformic acid

With salt of wormwood (2.26g, 16.4mmol) join 4-methyl hydroxybenzoate (1.0g, 6.6mmol) and cyclohexyl bromide (1.62ml, 13.1mmol) dimethyl formamide (20ml) solution in. in 100 ℃ with mixture heating up 24 hours, cooling, filter, vacuum concentration. handle after flash chromatography on silica gel (hexane: ethyl acetate, 5: 1) obtain 4-phenylcyclohexane methyl-formiate (169mg). with its (162mg, 0.69mmol) be dissolved in 1, in the mixed solution of 4-two _ alkane (10ml) and water (5ml), and the adding lithium hydroxide monohydrate (32mg, 0.76mmol).Under the room temperature mixed solution was stirred 18 hours.Add quantitative lithium hydroxide (32mg) again, continue to stir 4 hours.Mixed solution is joined in the ethyl acetate, use the salt water washing, concentrate the title compound (27mg) that obtains to yellow solid.

(ii) 6-methoxyl group-3-pyridine carboxylic acid

At 6-methoxyl group-3-pyridylaldehyde (50mg, 0.36mmol; According to Comins and Killpack at J.Org.Chem., 1990,55, the preparation of method described in the 69-73) the trimethyl carbinol (0.5ml) solution in add water (1.0ml) solution of potassium permanganate (81mg).At room temperature mixed solution was stirred 2 hours, add saturated sodium sulfite solution then and disappear until purple.With reaction mixture for several times, use dilute hydrochloric acid (2N) acidifying at last with chloroform extraction. the vacuum concentration chloroform extracted solution obtains title compound (42mg), is white solid.

(iii) 5-propionyl pyrazine carboxylic acid

In 0 ℃, with tert-butyl hydroperoxide (70%, 1.0ml, 7.25mmol) and FeSO ₄.7H ₂O (3.02g, water 10.9mmol) (8ml) solution join simultaneously 2-pyrazine carboxylic acid methyl esters (250mg, 1.81mmol) and propionic aldehyde (0.78ml is in sulfuric acid 0.9mmol) (0.75ml) solution.The reaction solution temperature to room temperature, was stirred 2 hours. add solid Na ₂S ₂O ₅(negative until starch/iodide test) uses the dichloromethane extraction mixed solution.Vacuum concentration, (use ethyl acetate: hexane (15: 85) wash-out) rapid column chromatography obtains 5-propionyl-2-pyrazine carboxylic acid, is light yellow solid (106mg) through silica gel.(25mg, tetrahydrofuran (THF) 0.6mmol) (15ml) and water (0.5ml) liquid are handled with LiOH with this methyl esters.After the room temperature 2 hours, with HCl (2N) acidification mixed liquor.Handle final vacuum and concentrate organic phase, obtain title compound (92mg).

(iv) 5,6,7,8-tetrahydroquinoline-3-formic acid

With 3-quinolinecarboxylic acid (1.73g, (20ml) mixed solution of trifluoroacetic acid 10.0mmol) and platinum dioxide (200mg) jolting under the 10-15psi in the Pa Er container.90 minutes after-filtration reaction mixtures, solvent removed in vacuo obtains oily matter.This oily matter is added drop-wise to generates white solid in the ether, filter and collect, obtain title compound (770mg), be white solid with the ethyl acetate/hexane recrystallization.

Embodiment 2: by method mutation (a) preparation I compound

Method A

In refluxing down, with the 3-quinolinecarboxylic acid (500mg, 2.89mmol), thionyl chloride (0.42ml, 5.8mmol) and the mixed solution of toluene (15ml) heated 2 hours.Cooling mixed liquid, solvent removed in vacuo obtains acyl chlorides, is white solid.

Under ice/water-bath cooling, (67mg adds acyl chlorides (41mg, 1.4 equivalents) in anhydrous methylene chloride 0.15mmol) (2ml) solution at amine VI.22.The solution that obtains is warmed to room temperature, restir 18 hours.Reaction mixture is diluted with methylene dichloride (30ml), and (solvent removed in vacuo obtains solid for 2 * 20ml) washings, dried over mgso, and flash chromatography (silica gel, ethyl acetate) purifying obtains 9616 (39mg, 44%), is white solid with saturated sodium carbonate solution.

When possible, directly buy acyl chlorides R ⁹-COCl. prepares other listed in the following table 11 compound by similar approach.

Method B

9653

Under the room temperature with amine VI.7 (165mg), 5-methylpyrazine formic acid (63mg, 1.2 cyclohexyl-N-(2-morpholino ethyl)-carbodiimide methyl-right-tosylate (162mg equivalent),, 1.0 equivalent) and anhydrous methylene chloride (15ml) solution stirring of I-hydroxybenzotriazole monohydrate (51mg, 1.0 equivalents) 18 hours.Then reaction mixture is diluted with methylene dichloride, water and saturated sodium carbonate solution washing, dried over mgso, solvent removed in vacuo obtains solid, and it is obtained 9653 (31mg) through flash chromatography (silica gel, ethyl acetate) purifying, is white solid.

By similar approach, other listed compound in the preparation following table 11.

Method C

9617

The 6-methylnicotinic acid (21mg, 0.15mmol) and amine VI.22 (50mg, add in anhydrous methylene chloride 0.11mmol) (2ml) solution iodate 2-chloro-1-picoline _ (41mg, 0.15mmol).Room temperature stirs mixed solution 7 days.Add saturated sodium carbonate solution (15ml), mixed solution is extracted twice with methylene dichloride (30ml).With the organic layer dried over mgso that merges, vacuum concentration. obtain 9617 (11mg, 18%) through flash chromatography on silica gel (ethyl acetate), be white solid.

By similar approach, other listed compound in the preparation following table 11.

Table 11

* in these embodiments, use acetonitrile to replace methylene dichloride down in room temperature to reflux temperature.

Reference example 7: intermediate formula XII bromide synthetic

Formula XIIa bromide is by being prepared as follows

At ice-cooled 7a, 4-oil of mirbane ethanol (5.0g, 29.9mmol) and imidazoles (2.25g, add in methylene dichloride 32.9mmol) (200ml) solution chlorination dimethyl hexyl (thexyl) silane (6.5ml, 33.2mmol).In room temperature reaction mixture was stirred 16 hours, use ether (200ml) dilution then.With ethereal solution water (200ml), 2N HCl (200ml) and salt solution (200ml) washing, dry (MgSO ₄), removal of solvent under reduced pressure obtains the compound 7b (10g) into yellow liquid.

7c

(10g adds PtO in EtOH 32.6mmol) (250ml) solution at 7b ₂(400mg), feed H then ₂Gas.With reaction mixture vigorous stirring 3 days, by diatomite filtration, removal of solvent under reduced pressure obtained the compound 7c (9.88g) into yellow liquid.

7d

(8.78g is 31.75mmol) with 2-nitrobenzoyl chloride (7.1g, CH 38.11mmol) at cold (0 ℃) 7d ₂Cl ₂(40ml) add NEt in the solution ₃(6.6ml 47.64mmol), after room temperature .16 hour, washs the reaction mixture temperature, with water lotion CH with reaction mixture water (40ml) ₂Cl ₂(2 * 40ml) strip. with the organic phase drying (MgSO that merges ₄), removal of solvent under reduced pressure obtains brown tarry solid.This solid stirred in hexane obtained white solid in 2 hours, filter, again it is dissolved in CH ₂Cl ₂In, filter by quick silica gel plug.Removal of solvent under reduced pressure obtains compound 7d (6g), is white solid.

7e

Press the described method of reduction of 7c, with EtOH (100ml) and PtO ₂(200mg) with 7d (5.0g, 11.7mmol) reduction.Obtain compound 7e (4.42g), be pink solid.

7f

(4.75g is 11.9mmol) with 3-quinoline formyl chlorine (2.7g, CH 14.3mmol) at 7e ₂Cl ₂(70ml) add NEt in the solution ₃(2.5ml, 17.9mmol). under the room temperature reaction mixture chamber was stirred 16 hours, pour into then in the sodium carbonate solution (70ml).Separate each layer, organic phase is washed with water, dry (MgSO ₄).Removal of solvent under reduced pressure obtains compound 7f (4.9g), is pale solid.

7g

At room temperature, (4.78g adds tetrabutylammonium (the THF liquid of 1M in THF 8.64mmol) (100ml) solution to 7f; 19.2ml, 17.28mmol), with this solution stirring 4 days.Removal of solvent under reduced pressure is dissolved in residue among the EtOAc (100ml), and the water that adds capacity is to produce precipitation.Filtering-depositing, first water is used Et again ₂The O washing.With residue and methylbenzene azeotropic, vacuum-drying obtains compound 7g (3g), is the paste solid.

XIIa

At 7g (3.0g, 7.29mmol) and triphenyl phosphine (3.8g, add in DMF 14.58mmol) (25ml) solution N-bromosuccinimide (2.6g, 14.58mmol). in 50 ℃, with reaction mixture heating 16 hours, cooling added MeOH (5ml) again and adds Et after .5 minute then ₂O is until precipitation occurring. filtering-depositing, use Et ₂The O washing. residue vacuum-drying is obtained compounds X IIa (2.13g), be pale solid.

Embodiment 3: by method mutation (b) preparation formula (I) compound

Flow process 3

Under the room temperature with 3a (i) (68mg, 0.35mmol) (be formula XX compound, by the following stated method preparation), XIIa (166mg, 0.35mmol), salt of wormwood (72mg, 0.52mmol) and the N of tetrabutylammonium iodide (0.1 equivalent), dinethylformamide (3ml) mixes molten stirring 4 days.Reaction mixture is diluted with ethyl acetate, wash with water, dried over mgso, solvent removed in vacuo obtain brown paste.Flash chromatography (silica gel, ethyl acetate) and recrystallization (methyl alcohol/methylene fluoride) obtain 9630 (43mg, 21%), are white solid.

Prepare following formula (I) compound with similar approach:

Method 3a (i)

(7.2ml, 0.052mol) with 3, (1.92ml, methylene dichloride 0.011mol) (10ml) solution join methyl-chloroformate, and (8ml in methylene dichloride 0.103mol) (50ml) solution, is cooled to-78 ℃ to the 4-dimethoxy-phenylethylamine with triethylamine.The reaction mixture temperature to room temperature, was stirred 18 hours.Pour into then in the saturated sodium carbonate solution, use dichloromethane extraction, dried over mgso, solvent removed in vacuo obtains yellow oil, and flash chromatography (acetic acid ethyl fluid of 1% methyl alcohol) purifying obtains Urethylane (2.06g, 78%).

(2.0g, tetrahydrofuran (THF) 8.37mmol) (60ml) drips of solution is added to lithium aluminum hydride, and (1.59g in the suspension of tetrahydrofuran (THF) 41.9mmol) (60ml), is cooled to 0 ℃ with Urethylane.The reaction mixture temperature to room temperature, was stirred 18 hours.Water (2.2ml) is added in the reaction mixture, add the 2N sodium hydroxide solution again, add entry (2.2ml) and sal epsom again.Stir after 15 minutes, filter mixed solution, the filtrate vacuum concentration is obtained 3a (i) (1.61g, 99%), be yellow oil.

Method 3a (iii)

With 3, the 4-mesitylenic acid (3.5g, 23.33mmol) and thionyl chloride (3.5ml, mixed solution 46.7mmol) are heated in toluene and refluxed 2 hours, cooling, solvent removed in vacuo obtains the crude product acyl chlorides into oily matter.It is dissolved in the methylene dichloride (50ml) the ice-cooled aqueous solution (18ml, 10 equivalents) that adds 40% methylamine down.Stir after 48 hours, the aqueous solution is handled and is obtained yellow solid, and it is obtained required acid amides (1.84g, 49%) through flash chromatography (silica gel, ethyl acetate/hexane) purifying, is white solid.

(1.00g adds lithium aluminum hydride (698mg, 2 equivalents) in anhydrous tetrahydro furan 6.13mmol) (20ml) solution, reaction mixture is heated to refluxed 3 hours at this acid amides.Cooling, the aqueous solution is handled and is obtained light oily matter, and it is obtained 3a (ii) (175mg, 19%) through flash chromatography (silica gel, ethyl acetate) purifying, is colorless oil.

Method 3a (iii)

In being cooled to 0 ℃ the vitriol oil (80ml), drip 1,2,3, and the 4-tetrahydroisoquinoline (20.2ml, 161mmol).Gradation carefully add saltpetre (17.5g, 173mmol).Stir after 16 hours, reaction mixture is alkalized with ammonium hydroxide solution,stronger, chloroform extraction, dried over mgso, solvent removed in vacuo obtains brown oil.It is dissolved in the ethanol (120ml), adds concentrated hydrochloric acid, filter and collect the precipitation that produces, obtain 3a hydrochloride (11.2g, 33%) (iii) with recrystallizing methanol.

Method 3a (iv), 3a (vi), 3a (vii), 3a (ix), 3a (x), 3a (xii), 3a (xiii And 3a (xiv)

Amine 3a (iv), (vi), (vii), 3a (ix), 3a (x), 3a (xii), 3a (xiii) and 3a (xiv) are prepared by suitable aromatic aldehyde reduction amination 3a 3a.It comprises reacts aldehyde and amine such as methylamine, ethamine or butylamine in appropriate solvent such as methyl alcohol or toluene.With the hydrogenation in appropriate solvent such as ethanol of platinum dioxide (IV) catalyzer, or in tetrahydrofuran (THF), the reduction of the imines that obtains is obtained required amine with lithium aluminum hydride.

Method 3a (v)

In acetonitrile with 3-hydroxyl-4-methoxybenzaldehyde (1.00g, 6.57mmol), 2-iodopropane (0.79ml, 1.2 equivalents) and salt of wormwood (1.09g, 1.2 equivalents) is heated to and refluxed 5 hours. the aqueous solution obtains required intermediate aldehydes after handling.By the (iv) described reduction amination of method 3a obtain required amine 3a (v). by similar method, aldehyde that can get with suitable commerce and alkylating reagent such as 1-butyl iodide or 2-iodopropane reaction, restore amination and become required amine, can prepare amine 3a (viii) and 3a (xi).

Method 3a (xv)

With 6,7-dimethoxy-1,2,3, (5.0g, excessive 48% Hydrogen bromide (80ml) 22mmol) and the solution of 50% diphosphanetetroic acid (0.4ml) mixed solution are heated to and refluxed 4 hours the 4-four hydrogen isoquinoline hydrochloric acid salt.The refrigerative reaction mixture is filtered,, obtain the compound (4.75g, 88%) of required dihydroxy, be white solid with methyl alcohol and ether washing.4: 1 acetone at this material (4.75g): add yellow soda ash (3.07g) in the solution of water mixed liquid, mixed solution is cooled off with ice bath.Add chloroformic acid benzyl ester (3.06ml) then, reaction mixture was stirred 18 hours, filter.Collect filtrate, after the aqueous solution was handled, flash chromatography (hexane/ethyl acetate) obtained benzyl carbamate (3.6g, 62%) with the ether grinding.

This benzyl carbamate (1g, N 3.34mmol), add in the dinethylformamide (50ml) methylene bromide (0.28ml, 3.99mmol) and salt of wormwood (2.75g, 19.7mmol), with mixed solution be heated to 100 ℃ 1.5 hours.After cooling and the filtration, collect filtrate, the aqueous solution is handled, and flash chromatography (5: 1 ethyl acetate of hexane) obtains 1,3 required dioxolane (669mg, 64%).

In the ethanol/methylene mixed solution, obtain required amine 3a (xv) at hydrocracking cracking benzyl carbamate on palladium-charcoal, under the normal pressure.

Method 3a (xvi)

At intermediate benzyl carbamate (above preparation) (500mg, 1.67mmol) tetrahydrofuran (THF) (10ml) solution in add the sodium hydride (dispersion liquid in 60% Dormant oils, 385mg, 10.03mmol), iodoethane (6.6ml, 83.6mmol) and methyl-sulphoxide (5ml).Reaction mixture is heated to backflow 18 hours.The aqueous solution is handled, and flash chromatography (5: 1 ethyl acetate of hexane) twice gets yellow oil (549mg, 92%).The same cracking benzyl carbamate obtains amine 3a (xvi).

Embodiment 4: the amine of through type VIII ' and formula R ⁵¹CO ₂The activated acids coupling preparation formula Ia compound of H (the method mutation (a '))

Method A

Quinoline-3-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides (9544)

In refluxing down, with the 3-quinolinecarboxylic acid (4.0g, 0.023mol), thionyl chloride (3.4ml, 0.046mol) and toluene (100ml) mixed solution heated 2 hours.Cooling mixed liquid, vacuum concentration obtains crude product acyl chlorides (4.15g) with the hexane grinding, is white solid.With under the ice/water-bath cooling, this acyl chlorides (2.64g, adding amine VIII.23 in anhydrous methylene chloride 14.0mmol) (100ml) suspension (4.0g, 9.3mmol).The solution that obtains is risen to room temperature, continue then to stir 1 hour.Add rare solution of potassium carbonate (100ml), with mixed solution chloroform extraction three times.With the organic layer exsiccant dried over mgso that merges, evaporation is until crystallization occurring.Add isopyknic ether, allow the mixed solution crystallization, 9544 (5.4g), be white solid.

Following table is listed other compound by the similar approach preparation.When possible, can directly buy acyl chlorides R ⁵¹-COCl.

Method B

Furans-3-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides (9526)

Under the room temperature, with 3-furans furancarboxylic acid (19mg, 0.17mmol), amine VIII ' .23 (75mg, 0.17mmol), cyclohexyl-N-(2-morpholino ethyl) carbodiimide methyl-right-tosylate (79mg, 0.19mmol) and I-hydroxybenzotriazole monohydrate (25mg, anhydrous methylene chloride 0.19mmol) (5.0ml) solution stirring 18 hours.Add saturated brine, mixed solution is extracted twice with methylene dichloride (25ml).With the organic layer exsiccant dried over mgso that merges, vacuum concentration.Through flash chromatography on silica gel (2% methyl alcohol, 98% ethyl acetate), obtain title compound 9526 (18mg) with re-crystallizing in ethyl acetate, be the yellow crystal solid.By other compound in the tabulation under the similar approach preparation.

Method C

N-(2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-6-methyl-niacinamide (9557)

The 6-methylnicotinic acid (47mg, 0.34mmol) and amine VIII ' .23 (75mg, add in anhydrous methylene chloride 0.17mmol) (5.0ml) solution triethylamine (0.05ml, 0.34mmol), add again iodate 2-chloro-1-picoline _ (44mg, 0.17mmol).Under the room temperature mixed solution was stirred 5 days.Add saturated sodium carbonate solution (15ml), mixed solution is extracted twice with methylene dichloride (30ml).With the organic layer exsiccant dried over mgso that merges, vacuum concentration.Through flash chromatography on silica gel (2% methyl alcohol, 98% ethyl acetate), obtain title compound (9557) (8mg) with the ether grinding, be white solid.

Method D

2-(4-sec.-propyl-benzamido)-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-3-methyl-benzamide (9398)

Thionyl chloride (5ml) is joined the 4-isopropyl acid, and (5.0g in toluene 0.03mol) (50ml) suspension, adds dimethyl formamide (1) again.Down mixed solution was heated 2 hours in refluxing, cooling, vacuum concentration obtains crude product acyl chlorides (5.5g), is yellow oil.With under the ice/water-bath cooling, with this acyl chlorides (68mg, 0.37mmol) join amine VIII ' .08 (110mg, 0.3mmol) with 2M sodium hydroxide mixed solution in.With the mixed solution temperature to room temperature, vigorous stirring 5 hours.Mixed solution is extracted twice with ethyl acetate (15ml), and salt solution (15ml) is once used dried over mgso, vacuum concentration.Through flash chromatography on silica gel (2% methyl alcohol, 98% methylene dichloride), obtain 9398 (16mg) with the ether grinding, be white solid.The residue recrystallization of mother liquor is obtained second batch of title compound (15mg).Prepare other compound in the table 12 by similar approach.

Table 12

Embodiment 5: the change of formula Ia compound

By the following stated, will change into other formula Ia compound by formula (Ia) compound of embodiment 4 described preparations.

(i) 2-(2-hydroxyl-aminobenzoic amido)-N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-phenyl }-benzamide (9535)

(0.035g adds sodium hydroxide (3mg, water 0.077mol) (0.5ml) solution in methyl alcohol 0.06mmol) (2ml) solution 9534.In room temperature mixed solution was stirred 2 hours, stirred 3 hours down in refluxing then.Add sodium hydroxide (0.18mol) again, continue to reflux 3 hours.With the mixed solution cooling, acidifying (2M HCl) is partly alkalized with saturated sodium bicarbonate solution.(2 * 25ml) extract, with salt brine solution (30ml) washing with ethyl acetate with mixed solution.With the organic phase dried over mgso, filter vacuum concentration.Chromatography (silica gel, ethyl acetate) obtains 9535 (19mg, 58%), is white solid.Other compound by the similar approach preparation is with 9540 preparations 9549, with 9548 preparations 9559.

(ii) 2-(4-sec.-propyl-benzamido)-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-5-phenyl-benzamide (9432)

(20mg, (5mg is 0.038mmol) with four (triphen is seen) palladium (2mg, glycol dimethyl ether 0.00173mmol) (0.5ml) and sodium carbonate solution (2M, 0.04ml, mixed solution 0.08mmol) 0.035mmol) to add phenyl-boron dihydroxide in the solution 9394.In refluxing down, with this mixed solution heating 3.5 hours.Cool off this mixed solution, add water (10ml).(2 * 15ml) extract, and dried over mgso is used in water (20ml) washing with ethyl acetate with mixed solution.Filter vacuum concentration.Chromatography (silica gel, ethyl acetate) obtains 9432 (15mg, 75%).

(iii) 2-(4-sec.-propyl-benzamido)-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-4-amino-benzamide (9435)

Platinum oxide (IV) (5mg) is joined 9420, and (47mg in the solution of methyl alcohol 0.086mmol) (2ml) and ethyl acetate (2ml), stirs mixed solution 18 hours under normal pressure hydrogen.Mixed solution is filtered by silica gel (10% methyl alcohol, 90% ethyl acetate), and vacuum concentration obtains 9435 (42mg, 95%), is yellow powder.

(iv) quinoxaline-2-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical-5-hydroxylamino-phenyl)-acid amides (9542)

Platinum oxide (IV) (4mg) is joined in the solution of the ethanol (25ml) of 9541 (38mg) and methylene dichloride (25ml), mixed solution was stirred 18 hours under normal pressure hydrogen.Mixed solution is passed through filtered through silica gel, vacuum concentration.Grind with ether (* 3) with ethyl acetate (* 1) back earlier, obtain 9542 (29mg, 80%), be yellow solid.

Embodiment 6 uses protecting group preparation formula (Ia) compound:

(a) by preparing 2-(4-sec.-propyl-benzamido)-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl shown in the flow process 4]-3-hydroxyl-benzamide (9424):

Step (i)

Under room temperature, the 3-hydroxyl anthranilic acid (324mg that commerce can be got, 2.12mmol), amine IX ' .a (500mg, 2.12mmol), N-cyclohexyl-N-(2-morpholino ethyl) carbodiimide methyl-right-tosylate (987mg, 2.33mmol), I-hydroxybenzotriazole monohydrate (315mg, 2.33mmol) and triethylamine (0.32ml, anhydrous methylene chloride 2.44ml) (20ml) solution stirring 3 days.The aqueous solution is handled, and through flash chromatography (2% methyl alcohol, 98% methylene dichloride, silica gel), obtains VIII ' .29 (174mg) after the grinding (ether), is orange solids.

Step (ii)

Under room temperature, with VIII.29 (170mg, 0.46mmol), imidazoles (34mg, 0.50mmol) and chlorination tertiary butyl dimethylsilane (76mg, dimethyl formamide 0.50mmol) (10ml) solution stirring 3 days.Add again a certain amount of chlorination tertiary butyl dimethylsilane (206mg, 1.37mmol) and imidazoles (93mg 1.37mmol), stirs mixed solution 4 hours.The aqueous solution is handled, and obtains VIII ' .30 (142mg) behind the flash chromatography (2% methyl alcohol, 98% ethyl acetate, silica gel), is yellow oil.

Step (iii)

Under ice/water-bath cooling, with triethylamine (1.12ml, 8.04mmol) and amine VIII ' .30 (1.57g, (by 9398 described preparations, 738mg is in anhydrous methylene chloride 4.04mmol) (20ml) 3.24mmol) to join the 4-isopropyl benzene formyl chloride of stirring.The mixed solution temperature to room temperature, was stirred 18 hours.Mixed solution is poured in the saturated sodium carbonate solution (50ml), extracted twice with methylene dichloride (75ml).With the organic extracting solution exsiccant dried over mgso that merges, vacuum concentration. flash chromatography (2% methyl alcohol, 98% ethyl acetate, silica gel) obtain 2-(4-sec.-propyl-aminobenzoic amido)-3-(tertiary butyl-dimethyl-silicon alkoxyl group)-N-[2-(6,7-dimethoxy-1,2,3,4-tetrahydrochysene-naphthalene-2-yl)-ethyl]-benzamide (367mg), be emulsifiable paste shape solid.

Step (iv)

Under with ice/water-bath cooling, with tetrabutylammonium (the tetrahydrofuran (THF) liquid of 1.0M, 0.63ml, 0.63mmol) join 2-(4-sec.-propyl-aminobenzoic amido)-3-(tertiary butyl-dimethyl-silicon alkoxyl group)-N-[2-(6,7-dimethoxy-1,2,3,4-tetrahydrochysene-naphthalene-2-yl)-ethyl]-(365mg is in tetrahydrofuran (THF) 0.58mmol) (20ml) solution for benzamide.Stir after 30 minutes, mixed solution is poured in the saturated ammonium chloride solution (30ml), extract twice with ethyl acetate (50ml).With organic layer water (50ml), salt solution (50ml) washing that merges, use the exsiccant dried over mgso, vacuum concentration.Flash chromatography (2% methyl alcohol, 98% ethyl acetate, silica gel) obtains 9424 (220mg), is light yellow solid.

(b) by prepare shown in the flow process 5 quinoxaline-2-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical-4-hydroxyl-phenyl)-acid amides (9554):

Flow process 5

Step (i)

Under ice-water bath cooling, with imidazoles (1.8g, 26.1mmol) and chlorination tertiary butyl dimethylsilane (3.95g, (1.0g is in dimethyl formamide 6.54mmol) (40ml) solution 26.1mmol) to join the 5-hydroxyl anthranilic acid that commerce provides.The mixed solution temperature to room temperature, was stirred 18 hours.The aqueous solution is handled and is obtained impure sample 2-amino-5-(tertiary butyl-dimethyl-silicon alkoxyl group)-phenylformic acid (1.74g), and it need not be further purified and be used for step (ii).

Step (ii)

With the 2-amino-5-in the step (i) (tertiary butyl-dimethyl-silicon alkoxyl group)-phenylformic acid (1.6g), amine IX.b (1.87g, 6.0mmol), N-cyclohexyl-N-(2-morpholino ethyl) carbodiimide methyl-right-tosylate (2.79g, 6.6mmol) and I-hydroxybenzotriazole monohydrate (0.89g, 6.6mmol) be dissolved in the anhydrous methylene chloride (50ml), under room temperature, stirred 3 days.After the aqueous solution was handled, flash chromatography (silica gel) obtained VIII ' .31 (443mg), is yellow foam.

Step (iii)

Under ice/water-bath cooling with 2-quinoxaline acyl chlorides (quinoxaloyl chloride) (67mg, 0.35mmol) join amine VIII ' .31 (200mg, 0.28mmol) and triethylamine (0.10ml is in anhydrous methylene chloride 0.72mmol) (10ml) solution.The mixed solution temperature to room temperature, was stirred 18 hours.The aqueous solution is handled; flash chromatography (silica gel; 2% methyl alcohol; 98% ethyl acetate) obtains quinoxaline-2-formic acid (4-(tertiary butyl-dimethyl-silicon alkoxyl group)-2-{4-[2-(6; 7-dimethoxy-3; 4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides (183mg), be yellow foam.

Step (iv)

Under with ice/water-bath cooling; tetrahydrofuran solution (1.0M with tetrabutylammonium; 0.067ml; 0.067mmol) join quinoxaline-2-formic acid (4-(tertiary butyl-dimethyl-silicon alkoxyl group)-2-{4-[2-(6; 7-dimethoxy-3; 4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-(150mg is in tetrahydrofuran (THF) 0.21mmol) (10ml) solution for acid amides.The mixed solution stirring after 30 minutes, is poured into mixed solution in the saturated ammonium chloride solution (20ml), extract twice with ethyl acetate (30ml).With organic phase water (30ml), salt solution (30ml) washing that merges, use the exsiccant dried over mgso, vacuum concentration.Flash chromatography (silica gel, 2% methyl alcohol, 98% ethyl acetate) obtains 9554 (32mg) with the ether grinding, is yellow solid.

(c) quinoline-3-formic acid (5-amino-2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical-phenyl)-acid amides (9589) is by preparation shown in the flow process 6.

Flow process 6

Step (i)

Under 20-25 ℃, with 4-amino-2-nitrobenzoic acid (0.96g, 5.3mmol), amine IX ' .b (1.65g, 5.3mmol), hydroxybenzotriazole monohydrate (0.79g, 5.8mmol), N-cyclohexyl-N-(2-morpholino ethyl) carbodiimide methyl-right-tosylate (2.46g, anhydrous methylene chloride 5.8mmol) (15ml) solution stirring 18 hours.Add entry (15ml), extract three times with methylene dichloride (15ml).With the organic extracting solution exsiccant dried over mgso that merges, vacuum concentration.Grind with ether, rapid column chromatography (10% methyl alcohol, 90% methylene dichloride) obtains intermediate nitra-amine (0.42g), is orange solids.

Step (ii)

Under ice/water-bath, with the product of step (i) (0.42g, 0.88mmol), two dimethyl dicarbonate butyl ester (0.24g, 1.10mmol) and N, (5mg, anhydrous methylene chloride 0.04mmol) (15ml) solution stirring 1 hour rose to the room temperature restir 3 days to the N-Dimethylamino pyridine.Add solution of potassium carbonate (15ml), extract mixture three times with methylene dichloride (15ml).With the organic layer exsiccant dried over mgso that merges, vacuum concentration.Chromatography (2.5% methyl alcohol, 97.5% methylene dichloride, silica gel) obtains the nitra-amine (0.37g) of intermediate protection.

Step (iii)

(0.35g adds 10% palladium-charcoal (35mg) in ethanol 0.61mmol) (5ml) and methylene dichloride (5ml) solution at this product.Under normal pressure hydrogen, mixed solution was stirred 18 hours.Pass through Celite ^TMFilter mixed solution, concentrate and occur until crystallization.Cooled product separates obtaining amine VIII.32 (0.19g), is the yellow crystal solid.

Step (iv)

Under ice/water-bath cooling, (192mg, (82mg is in anhydrous methylene chloride 0.43mmol) (3ml) suspension 0.35mmol) to join quinoline-3-formyl chloride with amine VIII.32.With the solution stirring that obtains 1 hour, rise to room temperature and continue to stir 18 hours.Add rare solution of potassium carbonate (30ml), mixed solution is extracted with chloroform (30ml).Organic phase is washed with water 4 times, use anhydrous magnesium sulfate drying, vacuum concentration.Grind with anhydrous diethyl ether, recrystallization (methyl alcohol, methylene dichloride) obtains product, and 9589 (0.19g) of Boc-protection are emulsifiable paste shape solid.

Step (v)

With above compound (78mg, the solution stirring of 5N hydrochloric acid (20ml) 0.11mmol) and ethanol (25ml) mixed solution 3 days.Mixed solution with the alkalization of unsaturated carbonate potassium solution, is extracted 3 times with methylene dichloride (50ml).With the organic phase exsiccant dried over mgso that merges, vacuum concentration.Flash chromatography (2.5% methyl alcohol, 97.5% methylene dichloride) obtains title compound with the ethanol/methylene recrystallization, and 9589 (15mg) are light brown solid.

Embodiment 7: by methyl o-aminobenzoate preparation formula Ia compound (method mutation (b))

The route of intermediate preparation formula (Ia) compound of through type XII ' is seen shown in the flow process 7:

Flow process 7

Doing to make commercial methyl o-aminobenzoate X ' that gets and formula R under solvent, the room temperature in the presence of the triethylamine, with methylene dichloride ⁵¹Obtained general formula X I intermediate in the acyl chloride reaction 1-14 of-COCl hour. in refluxing down, by with the methanol treatment solution of sodium hydroxide 1-5 hour with this intermediate ester XI ' hydrolysis. with mixed solution HCl acidifying, obtain the sour XII ' of intermediate after the processing.

The end product of preparation formula Ia by making acid and amine IX ' .a coupling.Add 1 in the THF of this intermediate acid solution, 1-carbonyl dimidazoles (1.1 equivalent) stirs mixed solution 1 hour in room temperature.In this mixed solution, add amine IX ' .a (1.0 equivalent) and tosic acid pyridine _ (2.6 equivalent).With the mixed-liquor return that obtains 56 hours, cooling.Remove and desolvate, after the processing, product flash chromatography purifying on silica gel.Compound by this logical method preparation is summed up in table 13.

Table 13

Embodiment 8: the azalactones preparation formula Ia compound by general formula X III ' (the method mutation (c '))

Flow process 8

Under 0 ℃, make commercial anthranilic acid that gets and formula R ⁵¹The acyl chlorides of-COCl middle reaction 3-8 hour, obtains the azalactones intermediate of formula XIII ' at pyridine or pyridine/methylene dichloride mixed solution.In the presence of tosic acid or camphorsulfonic acid, use amine Ix ' .a in backflow toluene, to handle 14-24 hour in this intermediate, obtain general formula I a compound.End product is through the flash chromatography on silica gel purifying.Pass through this path of preparing with following formula Ia compound:

Embodiment 9: the preparation of salt

The hydrochloride of formula (I) compound by with the THF solution of this compound with 2 moles salt acid treatment, supersound process prepares to obtaining settled solution again.Solvent removed in vacuo obtains hydrochloride with the residual solution lyophilize then.

In other method, hydrochloride is by HCl gas is fed in the THF solution of corresponding free alkali, and evaporate to dryness prepares again.

Embodiment 10: medicinal compositions

By being prepared as follows the tablet that sheet weighs 0.15g and contains the 25mg The compounds of this invention: 1000 composition

The compounds of this invention (250g)

Lactose (800g)

W-Gum (415g)

Talcum powder (30g)

Magnesium Stearate (5g)

Compound of the present invention, lactose and the W-Gum of half are mixed.Then mixture is crossed 0.5mm purpose sieve. W-Gum (10g) is suspended in the warm water (90ml). the paste that obtains is used for powder is granulated.With particle drying, broken at 1.4mm purpose plus sieve.Starch, talcum powder and the Magnesium Stearate of remainder are added careful mixing, compressing tablet.

Embodiment 11: the evaluation of formula (I) compound

The compound for preparing among the embodiment 2-9 is identified by the infrared technique under mass spectrum, trace analysis, proton magnetic resonance (PMR) and some situation.The result lists in following table.

Numbering	Molecular formula	Mass-spectrometric data		1The HNMR data
						Mass spectrum (intensity)	Mode	Solvent/field	d
		9304	C 30H 35N 3O 4 501	MH +502(70％)	CI					CDCl 3/400MHz	1.29 (6H, 2xd), 2.86 (6H, br.m), 3.0 (1H, septets), 3.68 (4H, m), 3.83 (3H, s), 3.86 (3H, s), 6.54 (1H, s), 6.62 (1H, s), 7.08 (1H, t), 7.16 (1H, br.s), 7.38 (2H, d), 7.51 (2H, t), 7.99 (2H, d), 8.82 (1H, d), 12.22 (1H, br.s)
9405	C 30H 34N 3O 4Cl 535/537					MH +536(15％) 206(100％)	EI	CDCl 3/400MHz	1.28(6H，d)，2.74-2.80(6H，m)2.95-3.04(1H，m， CH)3.60(2H，br.s)，3.65-3.70(2H，m)，3.81(3H，s， OMe)，3.83(3H，s，OMe)，6.49(1H，s)，6.58(1H，s)， 7.10(2H，d，J＝8Hz)，7.32-7.40(3H，m)，7.88(2H， d，J＝7Hz)，8.44(1H，d，J＝8Hz)，10.36(1H，br.s， NH)
		9354	C 30H 34N 3O 4Cl 535/537	MH +536(30％)	CI					CDCl 3/400MHz	1.28(6H，d，J＝7Hz)，2.75-2.85(6H，m)，2.95-3.02 (1H，m，CH)，3.62-3.66(4H，m)，3.84(3H，s，OMe)， 3.86(3H，s，OMe)，6.54(1H，s)，6.62(1H，s)，7.00 (1H，br.s，NH)，7.37(2H，d，J＝7Hz)，7.44-7.47 (2H，m)，7.95(2H，d，J＝7Hz)，8.80(1H，d，J＝ 8Hz)，12.01(1H，br.s，NH)
9350	C 30H 34ClN 3O 4					MH +536∶538-3∶1	ESI	CDCl 3/400MHz	1.29(6H，d)，2.90-3.42(8H，m)3.78-3.98(9H，m)，

	535.5	Ratio φ Cl cpd (100%)			6.55(1H，s)6.64(1H，s)，7.12(1H，d)，7.34(2H，d)， 7.84(1H，dd)，7.96(2H，d)，7.92-8.06(1H，br.m)， 8.95(1H，s)，12.48(1H，s)
						9401	C 30H 34ClN 3O 4 535.5g	MH +536/538[～3: 1 intensity, Clcpd] (47%) base peak 192 (100%)	EI	CDCl 3/400MHz	1.30(6H，d)，2.75-3.03(7H，m)3.58-3.68(2H，m)， 3.72(2H，br.s)，3.82(3H，s)，3.83(3H，s)，6.50(1H， s)，6.59(1H，s)，7.20(1H，t)，7.34(2H，d)，7.28-7.48 (1H，br.m)，7.50(1H，d)，7.54(1H，d)，7.92(2H，d)， 9.25(1H，s)
9394	C 30H 34N 3O 4Br 579/581	MH +580(15％) 206(70％)	EI	CDCl 3/400MHz	1.28(6H，d，J＝7Hz)，2.78-2.87(6H，m)，2.95-3.02 (1H，m，CH)，3.60-3.65(4H，m)，3.83(3H，s，OMe)， 3.85(3H，s，OMe)，6.54(1H，s)，6.62(1H，s)，6.90 (1H，br.s，NH)，7.36(2H，d，J＝7Hz)，7.55-7.60(2H， m)，7.94(2H，d，J＝7Hz)，8.74(1H，d，J＝8Hz)， 11.99(1H，br.s，NH)
						9349	C 31H 34FN 3O 4 519	MH +520(100％)	ESI	CDCl 3/400MHz	1.29 (6H, d), 2.83-3.10 (7H, m) 3.65-3.90 (10H, m), 6.54 (1H, s), 6.62 (1H, s), 6.77 (1H, t), 7.38 (2H, d), 7.67 (1H, br.s), 7.98 (2H, d), 8.67 (1H, dd), 12.53 (1H, s) and the NH signal that does not observe
9398	C 31H 37N 3O 4 515	MH +516 (24%) base peaks 206 (100%)	EI	CDCl 3/400MHz	1.28 (6H, d), 2.32 (3H, s), and 2.66-2.84 (6H, m), (2.97 1H, septet), 3.55 (2H, dd), 3.62 (2H, s), 3.83 (3H, s), 3.84 (3H, s), 6.51 (1H, s), 6.59 (1H, s), 6.95 (1H, br.s), 7.15 (1H, t), 7.28-7.40 (4H, m), 7.95 (2H, d)

					10.12(1H，s)
						9399	C 31H 37N 3O 5 531	MH +532 (10%) base peaks 192 (100%)	CI +	CDCl 3/400MHz	1.28 (6H, d), 2.60-2.82 (6H, m) 2.97 (1H, septet), and 3.50-3.60 (4H, m), 3.83 (3H, s), 3.84 (3H, s), 3.86 (3H, s), 6.48 (1H, s), 6.58 (1H, s), 6.93 (1H, br.s), 7.02 (1H, d), 7.12 (1H, d), 7.20 (1H, d), 7.32 (2H, d), 7.90 (2H, d), 8.94 (1H, s)
9424	C 30H 35N 3O 5 517	MH +518(100％)	CI +	CDCl 3/400MHz	1.28ppm (6H, s), 2.78-3.04 (6H, m), 2.98 (1H, septets), 3.60-3.86 (4H, m), 3.82 (3H, s) 3.83 (3H, s), 6.52 (1H, s), 6.60 (1H, s), 7.10-7.28 (3H, m), 7.38 (2H, d), and 7.40-7.64 (1H, br.s), 8.02 (2H, d), 10.18 (1H, s), 12.32 (1H, s)
						9420	C 30H 34N 4O 6	MH +，547(100％)	CI +	CDCl 3/400MHz	12.20 (1H, s), 9.68 (1H, d, J=1Hz), 7.96 (2H, d, J=8Hz), 7.84 (1H, dd, J=8Hz, 1Hz), 7.52 (1H, d, J=8Hz), 7.48 (2H, d, J=8Hz), 7.38 (1H, br.s), 6.62 (1H, s), 6.54 (1H, s), 3.86 (3H, s), 3.82 (3H, s), 3.72-3.54 (4H, m), 3.02 (1H, septets, J=7Hz), and 2.90-2.78 (6H, m), 1.30 (6H, d, J=7Hz)
9435	C 30H 36N 4O 4	MH +，517(100％)	CI +	CDCl 3/400MHz	12.70 (1H, s), 8.28 (1H, d, J=1Hz), 8.00 (2H, d, J=8Hz), 7.36 (2H, d, J=8Hz), 7.28 (1H, d, J=Hz), 6.88 (1H, Br.s), 6.64 (1H, s), 6.56 (1H, s), 6.30 (1H, dd, J=8Hz, 1Hz), 4.06 (2H, br.s), 3.88 (3H, s), 3.86 (3H, s), and 3.68-3.58 (4H, m), 3.00 (1H, septet, J=

					Hz)，2.90-2.74(6H，m)，1.30(6H，d，J＝7Hz)
						9432	C 36H 39N 3O 4 577	MH +，578(20％)	CI	CDCl 3/400MHz	1.28(6H，2xd，J＝7Hz)，2.80-2.85(6H，m)，2.94- 3.02(1H，m，CH)，3.62-3.70(4H，m)，3.80(3H，s， OMe)，3.82(3H，s，OMe)，6.52(1H，s)，6.60(1H，s)， 7.20(1H，b r.s，NH)，7.30-7.40(5H，m)，7.46(2H，d， J＝7Hz)，7.65-7.75(2H，m)，8.00(2H，d，J＝7Hz)， 8.87(1H，d，J＝8Hz)，12.12(1H，br.s，NH)
9410	C 34H 37N 3O 4 551	MH +552 (6%) base peaks 316 (100%)	EI	CDCl 3/400MHz	1.30(6H，d)，2.88-3.12(7H，m)3.70-3.89(10H，m)， 6.55(1H，s)，6.62(1H，s)，7.26(1H，s)，7.33-7.43 (3H，m)，7.52(1H，t)，7.82(2H，t)，8.03(2H，d)，8.32 (1H，br.s)，9.27(1H，s)，12.08(1H，s)
						9256.0	C 29H 34N 4O 4 ＝SO 2Da	SO 3DaMH +20％ 148Da100％ 267Da20％ 192Da45％	DCI +	CDCl 3/400MHz	2.76-2.87 (6H, m), 3.05 (6H, 2xs), and 3.61-3.68 (4H, m), 3.83 (3H, s), 3.86 (3H, s), 6.55 (1H, s), 6.62 (1H, s), 6.77 (2H, d), 6.95-7.04 (2H, overlapping t and br.s) and 7.43-7.50 (2H, m), 7.77 (2H, d) 8.80 (1H, d), 11.99 (1H, br.s)
9297.0 0	C 30H 35N 3O 5 501	MH +502(100％)	CI	CDCl 3/400.134 MHz	0.98 (3H, t), 1.68 (2H, sextets), 2.68 (2H, t), 2.74-2.85 (6H, m) 3.62 (4H, s and t), 3.81 (3H, s), 3.86 (3H, s), 6.54 (1H, s), 6.62 (1H, s), 7.02 (1H, br.s), 7.05 (1H, t), 7.31 (2H, d), 7.48 (1H, d), 7.5 (1H, t), 7.98 (2H, d), 8.8 (1H, d), 12.20 (1H, br.s) t is unintelligible
						9395	C 32H 39N 4O 3 529Da	MH +530Da(100％)	DCI +/ NH 3	CDCl 3/400MHz	0.92 (3H, t), 1.30-1.40 (4H, m) 1.42-1.69 (2H, water and sample signal are overlapping), 2.68 (2H, t), 2.85-2.97 (6H, m),

					3.67-3.79(4H，m)，3.82(3H，s)，3.87(3H，s)，6.53 (1H，s)，6.62(1H，s)，7.08(1H，t)，7.32(2H，d)，7.5- 7.65(2H，m)，7.98(2H，d)，8.82(1H，d)，12.24(1H， br.5)
						9331.0	C 33H 39N 4O 3 541Da	MH +542Da25％ 192Da100％ 102Da100％	DCI +	CDCl 3/400MHz	1.20-1.33 (1H, br.m), 1.42 (4H, br.m), 1.78 (1H, br.d), 1.89 (4H, br.m), 2.59 (1H, br.m), 2.89 (6H, m), (3.64-3.75 4H, signal overlap), 3.82 (3H, s), 3.86 (3H, s), 6.55 (1H, s), 6.63 (1H, s), 7.09 (1H, t), 7.35 (2H, d), 7.48-7.61 (2H, m), 7.79 (2H, d), 8.82 (1H, d), 12.21 (1H, br.s) NB: other NH signal is not seen
9294.0 0	C 33H 33N 3O 4 535	MH +536(100％)	CI	400.134MHz CDCl 3	2.82(6H，m)，3.65(2H，s)，3.68(2H，t)，3.82(3H，s)， 3.85(3H，s)，6.52(1H，s)，6.62(1H，s)，7.08(1H，br， s)，7.09(1H，t)，7.4(1H，t)，7.46(3H，m)，7.52(1H， t)，7.64(2H，d)，7.74(2H，d)，8.12(2H，d)，8.85(1H， d)，12.34(1H，s)
						9295.0 0	C 31H 31N 3O 4 509	MH +510(100％)	ESI	400.134MHz CDCl 3	2.81(6H，m)，3.65(2H，s)，3.66(2H，t)，3.82(3H，s)， 3.86(3H，s)，6.54(1H，s)，6.62(1H，s)，7.06(1H，br， s)，7.1(1H，t)，7.48-7.61(4H，m)，7.89(1H，d)7.96 (1H，d)，8.04(1H，d)，8.12(1H，d)，8.6(1H，s)，8.8 (1H，d)12.42(1H，s)
9302	C 28H 29N 3O 6	MH +(M-H) +	ESI	400.134MHz	2.86 (6H, br.m), 3.7 (4H, t and s) 3.86 (3H, s), 3.88

	503	50∶50 502(100％)			(3H，s)，6.05(2H，s)，6.55(1H，s)，6.61(1H，s)，6.91 (1H，d)，7.08(1H，t)，7.5(2H，t)，7.53(1H，d)，7.61 (1H，d)，8.79(1H，d)，12.2(1H，br.s)
						9310.0 0	C 31H 38N 4O 4 530	MH +(30％)	CI	400.134MHz	1.21(6H，t)，2.85(6H，m) +，3.42(4H，q)，3.68(4H， m) x，3.82(3H，s)，3.86(3H，s)，6.52(1H，s)，6.61(1H， s)，6.71(2H，d)，7.01(1H，t)，7.11(1H，br.s)，7.48 (2H，1Ht+d) *，7.94(2H，d)，8.82(1H，d)，11.98(1H， br.s) +Almost as triplet xIt should be triplet and unimodal *Possible triplet and bimodal overlapping
9334	C 31H 37N 4O 3 515	MH +516(100％)	CI	CDCl 3/400MHz	1.39 (9H, s), 2.79-2.91 (8H, m) 3.61-3.71 (2H, br.s), 3.81 (3H, s), 3.86 (3H, s), 6.54 (1H, s), 6.62 (1H, s), and 7.04-7.11 (1H, m), 7.46-7.56 (4H, m), 8.01 (2H, d), 8.82 (1H d) does not find the unintelligible spectrum of two NH protons
						9351	C 27H 29N 3O 4 459	MH +，460(100％)	ESI	CDCl 3/400MHz	2.75-2.85(6H，m)，3.62-3.65(4H，m)，3.82(3H，s， OMe)，3.85(3H，s，OMe)，6.53(1H，s)，6.60(1H， s)，7.04-7.10(2H，m)，7.45-7.55(5H，m)，8.03-8.06 (2H，m)，8.84(1H，d，J＝8Hz)，12.25(1H，br.s，NH)
9380	C 27H 28N 4O 3Br 538	MH +，538/540 1∶1(100％)	DCI+/-	CDCl 3/400MHz	2.95-3.07(6H，m)，3.74-3.86(10H，m)，6.54(1H，s)， 6.63(1H，s)，7.63(1H，t)，7.93(2H，d)，8.79(1H，d)，

					12.47 (1H br.s) does not find the NH proton
						9381	C 27H 28N 6O 4 SO 4Da	MH +505Da(100％)	DCI +	CDCl 3/400MHz	2.89-3.07(6H，m)，3.71-3.89(10H，m)，6.55(1H，s)， 6.66(1H，s)7.19(1H，t)，7.51-7.60(2H，m)，7.74 (1H，br.s)，8.22(2H，d)，8.37(2H，d)，8.84(1H，d)， 12.77(1H，br.s)
9426	C 33H 33N 3O 5 551	MH +552 (8%) base peaks 69 (100%)	CI +	CDCl 3/400MHz	2.80-3.00(6H，br.m)，3.60-3.90(10H，m)，6.53(1H， s)，6.62(1H，s)，7.06-7.12(6H，m)7.18(1H，t)，7.38 (2H，t)，7.50(1H，t)，7.62(1H，br.d)，8.03(2H，d)， 8.81(1H，d)，12.31(1H，s)
						9427	C 34H 33N 3O 5 563	MH +564 (32%) base peaks 328 (100%)	CI +	CDCl 3/400MHz	2.70-2.98(6H，br.m)，3.62-3.80(4H，m)，3.84(3H， s)，3.85(3H，s)，6.54(1H，s)，6.62(1H，s)，7.12(1H， t)，7.41(1H，br.s)，7.47-7.67(5H，m)，7.82(2H，d)， 7.92(2H，d)，8.14(2H，d)，8.85(1H，d)，12.54(1H， s)
9442	C 34H 35N 3O 4 549	MH +550(100％)	CI +	CDCl 3/400MHz	2.78-3.02(6H，br.)，3.60-3.78(4H，m)，3.86(3H，s)， 3.87(3H，s)，4.06(2H，s)，6.53(1H，s)，6.62(1H，s)， 7.08(1H，t)，7.12-7.65(10H，m)，7.97(2H，d)，8.82 (1H，d)，12.25(1H，s)
						9459	C 33H 39N 3O 5 557	MH +558(100％)	CI +	CDCl 3/400MHz	1.28-2.08(10H，m)，2.72-2.94(6H，m)，3.60-3.76 (4H，m)3.87(3H，s)，(3H，s)，4.35(1H，m)，6.53 (1H，s)，6.61(1H，s)，6.98(2H，d)，7.05(1H，t)，

					7.45-7.60(2H，m)，7.98(2H，d)，8.30(1H，d)，12.16 (1H，S)
						9460	C 34H 35N 3O 5 565	MH +566(100％)	CI +	CDCl 3/400MHz	2.70-2.88(6H，m)，3.58-3.68(4H，m)，3.85(3H，s)， 3.86(3H，s)，5.15(2H，s)，6.54(1H，s)，6.62(1H，s)， 6.95-7.55(11H，m)，8.04(2H，d)，8.80(1H，d)，12.18 (1H，s)
9377	C 26H 28N 4O 4 460	MH +461 (77%) base peaks 206 (100%)	CI +	CDCl 3/400MHz	2.70-2.95(6H，m)，3.62-3.90(10H，m)，6.52(1H，s)， 6.60(1H，s)，7.10(1H，t)，7.14-7.28(1H，br.m)，7.40- 7.62(3H，m)，7.88(1H，t)，8.28(1H，d)，8.78(1H， d)，8.86(1H，d)，12.94(1H，s)
						9359	C 26H 28N 4O 4 460	MH +461 (32%) base peaks 356 (100%)	CI +	CDCl 3/400MHz	2.75-2.95(6H，m)，3.60-3.77(4H，m)，3.84(3H，s)， 3.85(3H，s)，6.55(1H，s)，6.62(1H，s)，7.12(1H，t)， 7.40-7.62(4H，m)，8.32(1H，dt)，8.78(1H，dd)，8.82 (1H，d)，9.29(1H，s)，12.56(1H，s)
9384	C 26H 28N 4O 4 460	MH +461(100％)	ESI	CDCl 3/400MHz	2.76-2.94(6H，m)，3.60-3.72(4H，m)，3.85(3H，s)， 3.86(3H，s)，6.53(1H，s)，6.61(1H，s)，7.11(1H，t)， 7.33(1H，br.s)，7.50-7.60(2H，m)，7.89(2H，d)， 8.75-8.95(3H，m)12.67(1H，s)
						9391	C 28H 27N 5O 4	M +461 (8%) base peaks 206 (100%)	EI	CDCl 3/400MHz	2.75-2.90(6H，m)，3.60-3.24(4H，m)，3.84(3H，s)， 3.85(3H，s)，6.53(1H，s)，6.60(1H，s)，7.07-7.20 (2H，m)，7.47-7.59(2H，m)，8.75(2H，dd)，8.85(1H， d)，9.49(1H，s)，12.98(1H，s)

9347	C 29H 29N 5O 4 511	MH +512(100％)	CI +	CDCl 3/400MHz	2.75-3.00(6H，m)，3.70-3.90(10H，m)，6.52(1H，s)， 6.60(1H，s)，7.10-7.52(1H，br.m)，7.15(1H，t)，7.56 (1H，t)，7.65(1H，br.d)，8.82-8.94(2H，m)，8.15-8.40 (2H，m)，8.88(1H，d)9.74(1H，s)，13.14(1H，s)
						9383	C 30H 30N 4O 4 510	MH +511(100％)	ESI	CDCl 3/400MHz	2.80-2.95 (6H, m), 3.66-3.80 (4H, br.m), 3.83 (3H, s), 3.84 (3H, s), 6.51 (1H, s), 6.59 (1H, s), 7.12 (1H, t), 7.55 (1H, t), 7.60 (1H, br.d), 7.71 (2H, m), 7.83 (1H, d), 7.88 (1H, d), 8.69 (1H, d), 8.90 (1H, d), 9.53 (1H, d), 12.89 (1H, s) NH signal is not found.
9385	C 30H 30N 4O 4 510	MH +511(100％)	CI +	CDCl 3	2.70-3.05(6H，m)，3.70-3.90(10H，m)，6.45(1H，s)， 6.53(1H，s)，7.08(1H，t)，7.45(1H，br.s)，7.51(1H， t)，7.60-7.70(2H，m)，7.80(1H，t)，7.90(1H，d)， 8.32-8.42(3H，m)，8.87(1H，d)，13.13(1H，s)
						9389	C 30H 30N 4O 4 510	MH +511(100％)	EI	CDCl 3/400MHz	2.88(6H，br.s)，3.63-3.79(4H，m)，3.83(3H，s)，3.84 (3H，s)，6.51(1H，s)，6.61(1H，s)，7.11(1H，t)，7.16- 7.26(1H，m)7.53(1H，t)，7.60(1H，br.d)，7.70-7.82 (2H，m)，8.02(1H，d)，8.08(1H，d)，8.71(1H，s)，8.92 (1H，d)，9.37(1H，s)，13.07(1H，s)
9397	C 30H 30N 4O 4 510	MH +511 (14%) base peaks 207 (100%)	EI	CDCl 3/400MHz	2.77-2.93(6H，m)，3.60-3.75(4H，m)，3.82(3H，s)， 3.83(3H，s)，6.53(1H，s)，6.62(1H，s)，7.12(1H，t)， 7.31(1H，br.s)，7.50-7.68(3H，m)，7.83(1H，t)8.03 (1H，d)，8.19(1H，d)，8.80-8.90(2H，m)，9.55(1H，

					s)，12.72(1H，s)
						9365	C 25H 27N 3O 4S 510	MH +466(100％)	CI	CDCl 3/400MHz	2.77-2.85(6H，m)，3.63-3.68(4H，m)，3.84(3H，s， OMe)，3.86(3H，s，Ome)，6.53(1H，s)，6.60(1H，s)， 7.04-7.10(2H，m)，7.36-7.38(1H，m)，7.45-7.51 (2H，m)，7.63-7.65(1H，m)，8.10-8.12(1H，m)8.77 (1H，d，J＝Hz)，12.21(1H，br.s，NH)
9367	C 29H 30N 4O 4 498	MH +499(100％)	CI	CDCl 3/400MHz	2.80-2.86 (6H, m), 3.64-3.73 (4H, m), 3.84 (3H, s, OMe), 3.86 (3H, s, OMe), 6.55 (1H, s), 6.62 (1H, s), 7.05-7.10 (2H, m), and 7.15-7.20 (1H, m), 7.25-7.34 (2H, m is by CHCl 3Cover), and 7.44-7.55 (3H, m), 7.74 (1H, d, J=8Hz), 8.77 (1H, d, J=7Hz), 9.09 (1H, br.s.NH), 12.47 (1H, br.s, NH)
						9531	C 35H 33N 5O 4 587	MH +588(100％)	ESI	CDCl 3/400MHz	2.72-2.98(8H，m)，3.68(2H，s)3.84(3H，s)，3.85 (3H，s)，6.53(1H，s)，6.60(1H，s)，7.16-7.34(3H，m)， 7.55-7.64(3H，m)7.68(1H，d)，7.80-7.94(3H，m) 8.14-8.34(2H，d)，8.86(1H，d)9.75(1H，s)，12.65 (1H，br，s)
9542	C 35H 34N 6O 5	MH +619(100％)	ESI	d 6DMSO/400MHz	11.40(1H，s)，10.16(1H，s)，9.60(1H，s)，8.98(1H， s)，8.66(1H，s)，8.36(1H，s)，8.28-8.20(1H，m)， 8.18-8.10(1H，m)8.06-7.96(2H，m)，7.84(1H，d，J ＝8Hz)，7.68(2H，d，J＝8Hz，)，7.28(2H，d，J＝ 8Hz)，6.70-6.60(3H，m)，3.71(3H，s)，3.70(3H，s)，

					3.58(2H，s).2.88-2.80(2H，m)，2.78-2.66(6H，m)
						9543	C 36H 35N 5O 4 601	MH +602(100％)	ESI	CDCl 3/400MHz	2.41(3H，s)，2.70-2.98(8H，m)3.68(2H，s)，3.85 (3H，s)，3.86(3H，s)，6.54(1H，s)，6.60(1H，s)，7.28 (2H，d)，7.40(1H，d)，7.48(1H，s)，7.62(2H，d)， 7.80-7.95(3H，m)，8.12-8.32(2H，m)，8.70(1H，d)， 9.74(1H，s)，12.49(1H，br.s)
9554	C 35H 33N 5O 5 603	MH +604(100％)	ESI	DMSO/400MHz	2.55-2.87(8H，m)，3.45-3.77(8H，m)，6.63(2H，d)， 7.07(1H，d)，7.21-7.31(3H，m)，7.49(2H，d)，7.94- 8.24(4H，m)，8.44(1H，d)，9.57(1H，s)，9.87(1H，s)， 10.48(1H，br.s)，2.08(1H，br，s)
						9541	C 35H 32N 6O 6	MH +663(100％)	ESI	d 6DMSO/400MHz	11.98(1H，s)，10.84(1H，s)，9.4(1H，s)，9.56(1H，d， J＝2Hz)，8.28-8.00(6H，m)，7.74(2H，d，J＝8Hz)， 7.32(2H，d，J＝8Hz)，6.66(1H，s)，6.64(1H，s)，3.72 (3H，s)，3.71(3H，s)，3.58(2H，s)，2.90-2.80(2H，m)， 2.76-2.66(6H，m)
9561	C 36H 32F 3N 5O 4	MH +656(100％)	ESI	d 6DMSO/400MHz	12.00(1H，s)，10.74(1H，s)，9.60(1H，s)，9.08(1H， s)，8.24(1H，d，J＝8Hz)，8.18-8.08(2H，m)，8.06- 7.96(2H，m)，7.76-7.54(3H，m)，7.30(2H，d，J＝ 8Hz)，6.66(1H，s)，6.64(1H，s)，3.69(3H，s)，3.68 (3H，s)，3.54(2H，s)，2.88-2.78(2H，m)，2.76-2.62 (6H，m)
						9562	C 35H 32FN 5O 4	MH +606(100％)	ESI	d 6DMSO/400MHz	11.70(1H，s)，10.50(1H，s)，9.60(1H，s)，8.58(1H，

					dd，J＝2，12Hz)，8.24(1H，d，J＝8Hz)，8.18-8.10 (1H，m)，8.08-7.98(3H，m)，7.70(2H，d，J＝8Hz)， 7.28(2H，d，J＝8Hz)，7.24-7.14(1H，m)，6.66(1H， s)，6.64(1H，s)，3.71(3H，s)，3.70(3H，s)，3.56(2H， s)，2.88-2.78(2H，m)，2.76-2.64(6H，m)
						9564	C 35H 32FN 5O 4	MH +606(100％)	ESI	CDCl 3/400MHz	2.72-2.98(8H，m)，3.65(2H，s)3.85(3H，s)，3.86 (3H，s)，6.54(1H，s)，6.60(1H，s)，6.98(1H，dd)， 7.30(2H，d)，7.54(1H，dd)，7.64(2H，d)，7.82-7.94 (2H，m)，8.16-8.36(3H，m)，8.71(1H，d)，9.73(1H， s)，12.98(1H，br，s)
9568	C 38H 32FN 5O 4 605	MH +606(100％)	ESI	CDCl 3/400MHz	2.70-3.00(8H，m)，3.65(2H，s)3.85(3H，s)，3.86 (3H，s)，6.54(1H，s)，6.61(1H，s)，7.20-7.45(4H，m)， 7.60(2H，d)，7.80-7.95(3H，m)，8.12-8.32(2H，m)， 8.73-8.83(1H，m)，9.72(1H，s)，12.51(1H，br，s)
						9573	C 37H 37N 5O 6 647	MH +648(100％)	CI +	CDCl 3/400MHz	2.70-3.00(8H，m)，3.65(2H，s)3.85(3H，s)，3.86 (3H，s)，3.94(3H，s)，4.02(3H，s)，6.54(1H，s)，6.61 (1H，s)，7.13(1H，s)，7.28(2H，d)，7.59(2H，d)， 7.78-7.92(3H，m)，8.19(1H，d)，8.28(1H，d)，8.10 (1H，s)，9.72(1H，s)，12.79(1H，br，s)
9544	C 36H 34N 4O 4 586	MH +587(100％)	ESI	CDCl 3/400MHz	2.73-3.05(8H，m)，3.66(2H，s)3.86(3H，s)，3.87 (3H，s)，6.53(1H，s)，6.61(1H，s)，7.20(1H，t)， 7.23-7.37(2H，m)，7.52-7.74(5H，m)，7.83(1H，t)

					7.97-8.07(2H，m)，8.18(1H，d)8.80(1H，s)，8.85 (1H，d)，9.54(1H，s)，12.24(1H，br，s)
						9571	C 36H 33FN 4O 4	MH +605(100％)	CI +	d 6DMSO/400MHz	12.24(1H，s)，10.51(1H，s)，9.32(1H，d，J＝2Hz)， 8.90(1H，d，J＝2Hz)，8.38(1H，dd，J＝3，12Hz)， 8.18(1H，d，J＝8Hz)，8.14(1H，d，J＝8Hz)，8.08 (1H，dd，J＝7，9Hz)，7.92(1H，t，J＝8Hz)，7.74 (1H，t，J＝8Hz)，7.64(2H，d，J＝8Hz)，7.26(2H，d，J ＝8Hz)，7.24-7.18(1H，m)，6.64(1H，s)6.62(1H，s)， 3.69(3H，s)，3.68(3H，s)，3.53(2H，s)，2.86-2.78 (2H，m)，2.76-2.52(6H，m)
9574	C 36H 33FN 4O 4 604	MH +605(100％)	CI +	CDCl 3/400MHz	2.70-3.05(8H，m)，3.67(2H，s)3.85(3H，s)，3.86 (3H，s)，6.53(1H，s)，6.10(1H，s)，7.15-7.45(4H，m)， 7.52-7.70(3H，m)，7.84(1H，t)，8.00(1H，d)，8.18 (1H，d)，8.27(1H，br，s)，8.70-8.82(2H，m)，9.51 (1H，s)，11.98(1H，br.s)
						9581	C 36H 33N 5O 6	MH +632(100％)	ESI	d 6DMSO/400MHz	11.70(1H，s)，10.72(1H，s)，9.33(1H，s)，9.14(1H， s)，8.90(1H，d，J＝8Hz)，8.20-8.10(4H，m)，7.91 (1H，t，J＝8Hz)，7.72(1H，t，J＝8Hz)，7.64(2H，d，J ＝8Hz)，7.24(2H，d，J＝8Hz)，6.64(1H，s)，6.62 (1H，s)，3.69(3H，s)，3.68(3H，s)，3.53(2H，s)，2.84- 2.76(2H，m)，2.74-2.64(6H，m)
9545	C 36H 34N 4O 4	MH +587(100％)	ESI	CDCl 3/400MHz	2.68-2.98(8H，m)，3.66(2H，s)3.86(3H，s)，3.87(3H，

	586				s)，6.54(1H，s)，6.60(1H，s)，7.15(1H，t)， 7.38(2H，d)，7.55(1H，t)，7.58-7.72(4H，m)，7.80(1H， t)，7.89(1H，d)，8.02(1H，br.s)，8.28(1H，d)，8.32-8.40 (2H，m)，8.83(1H，d)，12.72(1H，br.s)
						9472	C 32H 32N 4O 4 536	MH +537(15％) 190(100％)	CI +	d 6DMSO/400MHz	12.26(1H，s)，10.48(1H，s)，8.74-8.70(1H，m)，8.68 (1H，d，J＝8Hz)，8.18(1H，d，J＝8Hz)，8.08(1H，t，J ＝8Hz)，7.88(1 H，d，J＝8Hz)，7.68-7.58(4H，m)， 7.30-7.22(3H，m)，6.68(1H，s)6.66(1H，s)，3.72 (3H，s)，3.71(3H，s)，3.54(2H，s)，2.86-2.78(2H，m)， 2.76-2.64(6H，m)
9482	C 32H 32N 4O 4 536	MH +537(100％)	ESI	CDCl 3/400MHz	2.75-2.95(8H，m)，3.65(2H，s)3.84(6H，2xs. 2xOMe)，6.54(1H，s)，6.60(1H，s)，7.15-7.20(1H， m)，7.28(2H，d，J＝7Hz)，7.41-7.46(1H，m)，7.52- 7.68(4H，m)，7.97(1H，NH)，8.26-8.30(1H，m)， 8.77-8.84(2H，m)，9.29(1H，s)，12.06(1H，br.s， NH)
						9483	C 32H 32N 4O 4 536	MH +537(100％)	ESI	CDCl 3/400MHz	2.76-2.95(8H，m)，3.65(2H，s)3.83(6H，2xs， 2xOMe)，6.52(1H，s)，6.59(1H，s)，7.07-7.12(1H， m)，7.28(2H，d，J＝7Hz)，7.48-7.55(3H，m)，7.65 (1H，d，J＝7Hz)，7.84(2H，d，J＝7Hz)，8.27(1H， br.s，NH)，8.74(1H，d，J＝8Hz)，8.82(2H，d，J＝ 7Hz)，12.10(1H，br.s，NH)

9493	C 31H 31N 5O 4 537	MH +538(100％)	ESI	CDCl 3/400MHz	2.73-2.93(8H，m)，3.64(2H，s)3.83(6H，2xs， xOMe)，6.53(1H，s)，6.60(1H，s)，7.20-7.28(3H， m)，7.52-7.63(3H，m)7.67(1H，d，J＝8Hz)，7.82 (1H，s)，8.69-8.71(1H，m)，8.75-8.77(1H，m)，8.83 (1H，d，J＝8Hz)，9.49(1H，s)，12.48(1H，br.s，NH)
						9527	C 32H 33N 5O 4 551	MH +552(100％)	ESI	CDCl 3/400MHz	2.65 (3H, s, Me), 2.75-2.95 (8H, m), 3.65 (2H, s), 3.84 (6H, 2xs, 2xOMe), 6.54 (1H, s), 6.60 (1H, s), and 7.15-7.20 (1H, m), 7.24-7.28 (2H, m is by CHCl 3Cover), and 7.54-7.60 (3H, m), 7.66 (1H, d, J=8Hz), 7.90 (1H, s), 8.54 (1H, s), 8.78 (1H, d, J=8Hz), 9.34 (1H, s), 12.39 (1H, br.s, NH)
9557	C 33H 34N 4O 4 550	MH +551(100％)	DCI	CDCl 3/400MHz	2.65(3H，s)，2.73-2.99(8H，m)3.64(3H，s)，3.84 (3H，s)，3.85(3H，s)，6.55(1H，s)，6.62(1H，s)，7.25- 7.35(4H，m)，7.53(2H，d)，7.60(1H，t)，7.69(1H， d)，7.89(1H，s)，8.18(1H，d)，8.84(1H，d)，9.17(1H， s)，12.03(1H，s)
						9582	C 33H 34N 4O 5 566	MH +567(100％)	ESI	d 6DMSO/400MHz	11.70(1H，br.s)，10.45(1H，br.s)，9.73(1H，d)，8.45 (1H，d)，8.15(1H，dd)，7.95(1H，d)，7.63-7.59(3H， m)，7.30-7.20(3H，m)，7.00(1H，d)，6.67(1H，s)， 6.64(1H，s)，3.92(3H，s)，3.70(3H，s)，3.69(3H，s)， 3.55(2H，s)，2.85-2.80(2H，m)，2.72-2.65(6H，m)
9569	C 34H 35N 5O 5	MH +594(50％)	CI	CDCl 3/400MHz	1.22-1.27(3H，t，Me)，2.75-2.95(8H，m)，3.25(2H，

	593				q，J＝8Hz，COCH 2), 3.66 (2H, s), 3.84 (3H, s, OMe), 3.85 (3H, s, OMe), 6.55 (1H, s), 6.62 (1H, s), (3H, m is by CHCl for 7.25-7.31 3Cover), and 7.53-7.65 (3H, m), 7.69 (1H, d, J=8Hz), 7.82 (1H, br.s, NH), 8.83 (1H, d, J=8Hz), 9.31 (1H, s), 9.48 (1H, s), 12.62 (1H, br.s, NH)
						9456	C 33H 33N 3O 4 535	M +536(100％)	CI	DMSO/400MHz	2.63-2.75(6H，m)，2.78-2.85(2H，m)，3.54(2H，s)， 3.68(6H，2xs)，6.63(2H，d)，7.21-7.3(3H，m)，7.52- 7.64(6H，m)，7.88-7.97(3H，m)，8.52(1H，d)，10.44 (1H，s)，11.78(1H，s)
9510	C 34H 35N 3O 4 549	MH +550(100％)	ESI	CDCl 3/400MHz	2.31(3H，s)，2.70-2.98(8H，m)，3.67(2H，s)，3.84 (3H，s)，3.85(3H，s)，6.55(1H，s)，6.60(1H，s)，6.81 (1H，d)，7.28(2H，d)，7.42-7.62(6H，m)，7.98-8.04 (2H，m)，8.26(1H，s)，8.57(1H，s)，11.80(1H，s)
						9511	C 34H 35N 3O 4 549	MH +550(100％)	CI +	CDCl 3/400MHz	2.25(3H，s)，2.70-2.98(8H，m)，3.67(2H，s)，3.85 (3H，s)，3.86(3H，s)，6.53(1H，s)，6.60(1H，s)，7.22- 7.34(3H，m)，7.39(3H，s)，7.45-7.63(5H，m)，8.02 (2H，d)，8.22(1H，s)，8.49(1H，d)，11.61(1H，br.s)
9512	C 34H 35N 3O 4 549	MH +550(100％)	CI +	CDCl 3/400MHz	2.50(3H，s)，2.65-2.98(8H，m)，3.66(2H，s)，3.82 (3H，s)，3.83(3H，s)，6.52(1H，s)，6.60(1H，s)，7.01 (1H，d)，7.23(2H，d)，7.32(1H，t)，7.40-7.60(5H， m)，7.80-7.90(3H，m)，8.06(1H，d)，9.32(1H，s)

9489	C 33H 32FN 3O 4	MH +554 (26%) fragments 435 (100%)	CI +	CDCl 3/400MHz	2.70-2.98(8H，m)，3.63(2H，s)，3.84(3H，s)，3.85 (3H，s)，6.53(1H，s)，6.60(1H，s)，7.10(1H，t)，7.17 (1H，dd)，7.20-7.64(8H，m)，8.03(1H，t)，8.12(1H， s)，8.63(1H，d)，11.37(1H，br.d)
						9500	C 33H 32FO 4 553	MH +554(100％)	CI +	CDCl 3/400MHz	2.70-2.98(8H，m)，3.65(2H，s)，3.83(3H，s)，3.84 (3H，s)，6.53(1H，s)，6.60(1H，s)，7.11(1H，t)， 7.20-7.32(3H，m)，7.40-7.80(7H，m)，8.09(1H，s)， 8.72(1H，d)，11.85(1H，s)
9501	C 33H 32N 3FO 4 553	MH +554(100％)	CI +	CDCl 3/400MHz	2.70-3.00(8H，m)，3.68(2H，s)，3.84(3H，s)，3.85 (3H，s)，5.54(1H，s)，6.60(1H，s)，7.05(1H，t)，7.18 (2H，t)，7.30(2H，d)，7.48(1H，t)，7.53-7.63(3H， m)，9.02(2H，q)，8.26(1H，s)，8.68(1H，d)，11.78 (1H，s)
						9513	C 33H 31F 2N 3O 4	MH +572(100％)	ESI	d 6DMSO/400MHz	11.38(1H，s)，10.44(1H，s)，8.42(1H，d，J＝8Hz)， 8.00-7.94(1H，m)，7.88(1H，d，J＝8Hz)，7.64-7.56 (3H，m)，7.48-7.40(1H，m)，7.34-7.20(4H，m)6.66 (1H，s)，6.64(1H，s)，3.79(3H，s)，3.71(3H，s)，3.54 (2H，s)，2.84-2.76(2H，m)，2.74-2.52(6H，m)
9514	C 33H 31F 2N 3O 4	MH +572(100％)	ESI	d 6DMSO/400MHz	11.28(1H，s)，10.38(1H，s)，8.30(1H，d，J＝8Hz)， 7.84(1H，d，J＝8Hz)，7.62-7.52(4H，m)，7.32(1H，t， J＝8Hz)，7.26-7.18(4H，m)，6.66(1H，s)，6.64(1H， s)，3.72(3H，s)，3.71(3H，s)，3.54(2H，s)，2.84-2.78

					(2H，m)2.76-2.62(6H，m)
						9494	C 33H 32ClN 3O 4	MH +570，572 (100％；3∶1)	CI +	d 6DMSO/400MHz	11.14(1H，s)，10.38(1H，s)，8.32(1H，d，J＝8Hz)， 7.86(1H，d，J＝8Hz)，7.68-7.42(7H，m)，7.32(1H，t， J＝8Hz)，7.22(2H，d，J＝8Hz)，6.66(1H，s)，6.64 (1H，s)，3.68(3H，s)，3.67(3H，s)，3.52(2H，s)，2.82- 2.76(2H，m)2.74-2.50(6H，m)
9495	C 33H 32ClN 3O 4	MH +570，572 (100％；3∶1)	CI +	d 6DMSO/400MHz	11.68(1H，s)，10.44(1H，s)，8.38(1H，d，J＝8Hz)， 7.92-7.80(3H，m)，7.68-7.56(5H，m)7.36-7.20(3H， m)，6.66(1H，s)6.64(1H，s)，3.72(3H，s)，3.71(3H， s)，3.54(2H，s)，2.84-2.76(2H，m)，2.74-2.52(6H，m)
						9496	C 33H 32ClN 3O 4	MH +570，572 (100％；3∶1)	CI +	d 6DMSO/400MHz	11.78(1H，s)，10.46(1H，s)，8.46(1H，d，J＝8Hz)， 7.96-7.88(3H，m)，7.68-7.56(5H，m)，7.32-7.20 (3H，s)，6.66(1H，s)6.64(1H，s)，3.72(3H，s)，3.71 (3H，s)，3.54(2H，s)，2.86-2.78(2H，m)2.76-2.64 (6H，m)
9497	C 34H 35N 3O 4	MH +550(100％)	ESI	d 6DMSO/400MHz	11.06(1H，s)，10.38(1H，s)，8.38(1H，d，J＝8Hz)， 7.86(1H，d，J＝8Hz)，7.62-7.56(3H，m)，7.52(1H， d，J＝8Hz)，7.40(1H，t，J＝8Hz)，7.34-7.26(3H，m)， 7.22(2H，d，J＝8Hz)，6.66(1H，s)，6.64(1H，s)，3.72 (3H，s)，3.71(3H，s)，3.52(2H，s)，2.80-2.74(2H，m)， 2.72-2.60(6H，m)，2.40(3H，s)
						9503	C 34H 35N 3O 4	MH +550(100％)	ESI	d 6DMSO/400MHz	11.68(1H，s)，10.44(1H，s)，8.48(1H，d，J＝8Hz)，

					7.90(1H，d，J＝8Hz)，7.76(1H，s)，7.70(1H，d，J＝ 8Hz)，7.66-7.58(3H，m)，7.48-7.38(2H，m)，7.30- 7.22(3H，m)，6.66(1H，s)，6.64(1H，s)，3.72(3H，s)， 3.71(3H，s)，3.54(2H，s)，2.84-2.78(2H，m)，2.76- 2.62(6H，m)，2.38(3H，s)
						9504	C 34H 35N 3O 4	MH +550(100％)	ESI	d 6DMSO/400MHz	11.78(1H，s)，10.46(1H，s)，8.52(1H，d，J＝8Hz)， 7.92(1H，d，J＝8Hz)，7.82(2H，d，J＝8Hz)，7.64- 7.56(3H，m)，7.38(2H，d，J＝8Hz)，7.30-7.22(3H， m)，6.66(1H，s)，6.64(1H，s)，3.72(3H，s)，3.71(3H， s)，3.54(2H，s)，2.86-2.78(2H，m)，2.76-2.64(6H， m)，2.38(3H，s)
9477	C 34H 35N 3O 5 565	MH +566(100％)	CI +	CDCl 3	2.70-2.98(8H，m)，3.65(2H，s)3.85(3H，s)，3.86 (3H，s)，4.02(3H，s)，6.55(1H，s)，6.60(1H，s)，6.98 (1H，d)，7.02-7.12(2H，m)，7.20-7.32(2H，m)7.42- 7.50(2H，m)，7.55(1H，d)7.60(2H，d)，8.06(1H，s)， 8.22(1H，d)，8.65(1H，d)，11.54(1H，s)
						9517	C 34H 35N 3O 5 565	MH +566(100％)	ESI	CDCl 3/400MHz	2.76-2.95 (8H, m), 3.65 (2H, s) 3.84 (6H, 2xs, 2xOMe), 3.89 (3H, s, OMe), 6.54 (1H, s), 6.61 (1H, s), 7.05-7.10 (1H, m), and 7.14-7.19 (1H, m), 7.26-7.30 (2H, m is by CHCl 3Cover), and 7.38-7.42 (1H, m), 7.52-7.60 (5H, m) 7.66 (1H, d, J=8Hz), 7.92 (1H, s, NH), 8.80 (1H, d, J=8Hz), 11.80 (1H, br.s, NH).

9518	C 34H 35N 3O 5 565	MH +566(100％)	ESI	CDCl 3/400MHz	2.75-2.95(8H，m)，3.64(2H，s)3.83(6H，2xs， 2xOMe)，3.87(3H，s，OMe)，6.53(1H，s)，6.60(1H， s)，6.98(2H，d，J＝7Hz)，7.04-7.09(1H，m)，7.28 (2H，d，J＝7Hz)，7.48-7.63(4H，m)，7.99(2H，d，J＝ 7Hz)，8.09(1H，s，NH)，8.75(1H，d，J＝8Hz)，11.65 (1H，br.s，NH)
						9535	C 33H 33N 3O 5 551	MH +552(100％)	CI	CDCl 3/400MHz	2.74-2.94(8H，m)，3.65(2H，s)3.83(6H，2xs， 2xOMe)，6.54(1H，s)，6.60(1H，s)，6.91-7.00(2H， m)，7.20-7.30(3H，m)，7.40-7.44(1H，m)，7.53(2H， d，J＝7Hz)，7.59-7.63(1H，m)，7.70(1H，d，J＝ 8Hz)，7.78(1H，d，J＝8Hz)，7.85(1H，s)，8.71(1H， d，J＝8Hz)，12.08(1H，br.s，NH)，12.22(1H，s)
9549	C 33H 33N 3O 5 551	MH +552(100％)	ESI	CDCl 3/400MHz	2.74-2.95(8H，m)，3.64(2H，s)3.83(3H，s，OMe)， 3.85(3H，s，OMe)，6.52(1H，s)，6.59(1H，s)6.98- 7.01(1H，m)，7.14-7.17(1H，m)，7.23-7.28(2H，m)， 7.34-7.38(1H，s)，7.42-7.60(6H，m)，7.65(1H，d，J ＝8Hz)，7.87(1H，s)，8.81(1H，d，J＝8Hz)，11.74 (1H，br.s，NH)

9559	C 33H 33N 3O 5 551	MH +552(100％)	ESI	CDCl 3/DMSO/400 MHz	2.76-2.94(8H，m)，3.65(2H，s)3.83(6H，2xs， 2xOMe)，6.55(1H，s)，6.62(1H，s)，6.93(2H，d，J＝ 7Hz)，7.12-7.16(1H，m)，7.26(2H，d，J＝7Hz)， 7.50-7.57(1H，m)，7.60(2H，d，J＝7Hz)，7.73-7.76 (1H，m)，7.90(2H，d，J＝8Hz)，8.78(1H，d，J＝ 8Hz)，8.93(1H，s)，9.10(1H，br.s)，11.69(1H，s，NH)
						9534	C 35H 35N 3O 6 593	MH +594(100％)	ESI	CDCl 3/400MHz	2.31 (3H, s, Ac), 2.73-2.93 (8H, m), 3.64 (2H, s), 3.84 (6H, 2xs, 2xOMe), 6.53 (1H, s), 6.60 (1H, s), and 7.14-7.19 (2H, m), 7.24-7.27 (2H, m is by CHCl 3Cover), and 7.32-7.36 (1H, m), 7.49-7.58 (4H, m), 7.63 (1H, d, J=8Hz), 7.85-7.92 (2H, m), 8.69 (1H, d, J=8Hz), 11.29 (1H, br.s, NH)
9540	C 35H 35N 3O 6 593	MH +594(100％)	ESI	CDCl 3/400MHz	2.32(3H，s，Ac)，2.76-2.96(8H，m)，3.65(2H，s)， 3.83(6H，2xs，2xOMe)，6.53(1H，s)，6.60(1H，s)， 6.98-7.01(1H，m)，7.27-7.31(3H，m)，7.39-7.45 (1H，m)，7.49-7.64(4H，m)，7.77-7.79(1H，m)，7.84 (1H，d，J＝7Hz)，8.45(1H，s，NH)，8.62(1H，d，J＝ 8Hz)，11.72(1H，s，NH)
						9548	C 35H 35N 3O 6 593	MH +594(100％)	ESI	CDCl 3/400MHz	2.32(3H，s，Ac)，2.75-2.95(8H，m)，3.65(2H，s)， 3.84(6H，2xs，2xOMe)，6.53(1H，s)，6.60(1H，s)， 7.10-7.15(1H，m)，7.20-7.30(4H，m)，7.52-7.56 (3H，m)，7.64(1H，d，J＝8Hz)，8.00-8.06(3H，m)，

					8.77(1H，d，J＝8Hz)，11.82(1H，s，NH)
						9523	C 34H 32F 3N 3O 4	MH +604(100％)	ESI	d 6DMSO/400MHz	11.10(1H，s)，10.48(1H，s)，8.26(1H，d，J＝8Hz)， 7.86(2H，d，J＝8Hz)，7.84-7.68(3H，m)，7.64-7.54 (3H，m)，7.34(1H，t，J＝8Hz)，7.22(2H，d，J＝8Hz)， 6.66(1H，s)，6.64(1H，s)，3.72(3H，s)，3.71(3H，s)， 3.54(2H，s)，2.84-2.76(2H，m)，2.74-2.52(6H，m)
9524	C 34H 32F 3N 3O 4	MH +604(100％)	ESI	d 6DMSO/400MHz	11.70(1H，s)，10.42(1H，s)，8.36(1H，d，J＝8Hz)， 8.24(1H，s)，8.18(1H，d，J＝8Hz)，7.98(1H，d，J＝ 8Hz)，7.90(1H，d，J＝8Hz)，7.84(1H，t，J＝8Hz)， 7.66-7.58(3H，m)，7.34(1H，t，J＝8Hz)，7.24(2H， d，J＝8Hz)，6.66(1H，s)，6.64(1H，s)，3.72(3H，s)， 3.71(3H，s)，3.56(2H，s)，2.86-2.78(2H，m)，2.74- 2.52(6H，m)
						9556	C 35H 37N 4O 4	MH +579(32％)	ESI	CDCl 3/400MHz	2.70-2.98 (8H, m), 3.03 (6H, two coincidences unimodal), 3.66 (2H, s), 3.85 (3H, s), 3.86 (3H, s), 6.54 (1H, s), 6.60 (1H, s), 6.89 (1H, d), 7.08 (1H, t), 7.20-7.42 (4H, m), 7.49 (1H, t) 7.52-7.64 (3H, m), 8.15 (1H, s) 8.74 (1H, d), 11.65 (1H, br.s)
9447	C 36H 39N 3O 4 577	MH +578(100％)	CI	CDCl 3/400MHz	1.28(6H，2xd，J＝7Hz)，2.74-3.01(9H，m)，3.65 (2H，br.s)，3.84(6H，2xs，2xOMe)，6.53(1H，s)， 6.60(1H，s)，7.05-7.10(1H，m)，7.25-7.35(4H，m) 7.48-7.65(4H，m)，7.93(2H，d，J＝7Hz)，8.08(1H，

					s)，8.75(1H，d，J＝8Hz)，11.68(1H，br.s，NH)
						9461	C 39H 43N 3O 4 617	MH +618	CI	CDCl 3/400MHz	1.34-1.93(10H，m)，2.52-2.62(1H，m，CH)，2.76- 2.95(8H，m)，3.65(2H，s)，3.83(6H，2xs，2xOMe)， 6.55(1H，s)，6.59(1H，s)，6.95-7.00(1H，m)，7.25- 7.35(4H，m)，7.40-7.45(1H，m)7.55-7.62(3H，m)， 7.90(2H，d，J＝7Hz)，8.37(1H，s，NH)，8.65(1H，d， J＝8Hz)，11.60(1H，br.s，NH)
9470	C 37H 35N 3O 4 585	MH +586(100％)	CI +	CDCl 3/400MHz	2.66-2.94(8H，m)，3.62(2H，s)3.82(3H，s)，3.83 (3H，s)，6.52(1H，s)，6.59(1H，s)，7.10-7.70(10H，m)， 7.86(2H，dd)，7.95(2H，s)，8.53(1H，d)，8.87(1H， d)，11.33(1H，s)
						9476	C 37H 35N 3O 4 585	MH +586(15％)	CI	CDCl 3/400MHz	2.77-2.97(8H，m)，3.63(2H，s)3.84(6H ，2xs， 2xOMe)，6.53(1H，s)，6.60(1H，s)，7.10-7.16(1H， m)，7.29(2H，d，J＝7Hz)，7.54-7.61(5H，m)，7.67 (1H，d，J＝8Hz)，7.87-8.09(5H，m)，8.55(1H，br.s， NH)，8.83(1H，d，J＝8Hz)，11.95(1H，br.s，NH)
9536	C 33H 31Cl 2N 3O 4 603	MH +604/606/608 (100%) 9: 6: 1 intensity φ Cl 2cpd	ESI	CDCl 3	2.70-2.98(8H，m)，3.66(2H，s)3.87(3H ，s)，3.88 (3H，s)，6.55(1H，s)，6.60(1H，s)，7.17(1H，t)，7.30 (2H，d)，7.48-7.60(4H，m)，7.65(1H，d)，7.80(1H， d)，8.02(1H，br.s)，8.13(1H，d)，8.74(1H，d)，11.95 (1H，br.s)
						9538	C 35H 37N 3O 4	MH +564(100％)	ESI	CDCl 3	2.34(3H，s)，2.36(3H，s)，2.72-2.98(8H，m)，3.66

	563				(2H，s)，3.83(3H，s)，3.84(3H，s)，6.55(1H，s)，6.61 (1H，s)，7.03(1H，t)，7.20-7.34(3H，m)，7.45(1H，t)， 7.54-7.62(3H，m)，7.70(1H，d)，7.80(1H，s)，8.25 (1H，s)，8.68(1H，s)，11.59(1H，s)
						9471	C 31H 31N 3O 4S	MH +542(6％) 230(100％)	CI +	d 6DMSO/400MHz	11.68(1H，s)，10.46(1H，s)，8.40(1H，d，J＝8Hz)， 7.96(1H，d，J＝8Hz)，7.88(1H，d，J＝3Hz)，7.74 (1H，d，J＝2Hz)，7.66-7.56(3H，m)，7.30-7.70(4H， m)，6.66(1H，s)，6.64(1H，s)，3.72(3H，s)，3.71(3H， s)，3.56(2H，s)，2.86-2.78(2H，m)，2.76-2.64(6H，m)
9492	C 31H 31N 3O 4S 541	MH +542(100％)	ESI	CDCl 3/400MHz	2.75-2.95(8H，m)，3.65(2H，s)3.83(6H，2xs， 2xOMe)，6.53(1H，s)，6.60(1H，s)，7.10-7.15(1H， m)，7.29(2H，d，J＝7Hz)，7.36-7.39(1H，m)，7.51- 7.66(5H，m)，7.94(1H，s，NH)，8.09-8.11(1H，m)， 8.79(1H，d，J＝8Hz)，11.74(1H，br.s，NH)
						9526	C 31H 31N 3O 5 525	MH +526(100％)	CI +	CDCl 3/400MHz	2.72-2.98(8H，m)，3.67(2H，s)3.85(3H，s)，3.86 (3H，s)，6.55(1H，s)，6.62(1H，s)，6.86(1H，s)，7.60 (1H，t)，7.28(2H，d)，7.42-7.62(5H，m)，8.08(2H，d) 8.70(1H，d)，11.55(1H，br.s)
9515	C 35H 34N 4O 4	MH +575(100％)	ESI	d 6DMSO/400MHz	11.76(1H，s)，11.34(1H，s)，10.44(1H，s)，8.58(1H， d，J＝8Hz)，8.18(1H，d，J＝8Hz)，7.98(1H，s)， 7.90(1H，d，J＝8Hz)，7.64(2H，d，J＝8Hz)，7.58 (1H，t，J＝8Hz)，7.50(1H，d，J＝8Hz)，7.30-7.16

					(5H，m)，6.66(1H，s)，6.64(1H，s)，3.72(3H，s)，3.71 (3H，s)，3.54(2H，s)，2.86-2.78(2H，m)，2.74-2.64 (6H，m)
						9539	C 35H 33N 3O 5 575	MH +576(100％)	CI +	CDCl 3/400MHz	2.70-3.00(8H，m)，3.67(2H，s)3.83(3H，s)，3.84 (3H，s)，6.54(1H，s)，6.61(1H，s)，7.15(1H，t)，7.22- 7.37(3H，m)，7.43(1H，t)，7.48-7.74(7H，m)，8.02 (1H，br.s)，8.74(1H，d)，11.89(1H，br.s)
9466	C 34H 41N 3O 4 555	MH +556(100％)	ESI	CDCl 3/400MHz	1.24-1.51(5H，m)，1.75-1.95(7H，m)，2.52-2.60(1H， m，CH)，2.78-2.83(6H，m)，3.59-3.67(4H，m)，3.83 (3H，s，OMe)，3.89(3H，s，OMe)，6.24-6.27(1H， m)，6.54(1H，s)，6.63(1H，s)，7.03(1H，d，J＝8Hz)， 7.27-7.34(3H，m)，7.96(2H，d，J＝7Hz)，8.74(1H， d，J＝8Hz)，9.36(1H，br，s，NH).12.62(1H，br，s， NH)
						9479	C 31H 35N 3O 2 481	MH +482(100％)	CI +	CDCl 3/400MHz	1.20-2.00(10H，m)，2.50-2.62(1H，m)，2.70-2.98 (6H，m)，3.65(2H，q)，3.72(2H，s)，6.95-7.55(10H， m)，7.98(2H，d)，8.80(1H，d)，12.18(1H，s)
9567	C 36H 35N 5O 4 601	MH +602(100％)	CI +	CDCl 3/400MHz	1.85-2.00(2H，m)，2.55(2H，t)，2.60-2.88(6H，m)， 3.54(2H，s)，3.82(3H，s)，3.83(3H，s)，6.52(1H，s)， 6.60(1H，s)，7.18-7.32(3H，m)，7.56-6.65(3H，m)， 7.60(1H，d)7.82-7.94(3H，m)，8.14-8.36(2H，m)， 8.85(1H，d)，9.73(1H，s)，12.67(1H，br，s)

9572	C 34H 31N 3O 4 573	MH +574(100％)	CI +	CDCl 3/400MHz	2.70-2.90(4H，m)，3.55(2H，s)，3.69(2H，s)，3.79 (3H，s)，3.83(3H，s)，6.49(1H，s)，6.61(1H，s)，7.22 (1H，t)，7.45(2H，d)，7.60(1H，t)，7.64-7.74(3H，m) 7.80-7.92(2H，m)，8.01(1H，br，s)，8.12-8.34(2H， m)，8.85(1H，d)，9.74(1H，s)，12.72(1H，br，s)
						9577	C 34H 30N 4O 2 526	MH +572(100％)	DCI +/ NH 3	CDCl 3/400MHz	12.25(1H，s)，9.55(1H，d)，8.85(1H，d)，8.81(1H， d)，8.20(1H，d)，8.05-8.00(2H，m)，7.85-7.81(1H， m)，7.71-7.60(3H，m)，7.57(2H，d)，7.31(2H，d)， 7.19(1H，t)，7.14-7.09(3H，m)，7.05-7.02(1H，m)， 3.75(2H，s)，2.98-2.92(4H，m)2.85-2.77(4H，m)
9576	C 38H 38N 4O 6 646	MH +647(100％)	ESI	CDCl 3/400MHz	2.75-3.05(8H，m)，3.70(2H，s)，3.86(3H，s)，3.87 (3H，s)，3.94(3H，s)，4.03(3H，s)，6.54(1H，s)，6.61 (1H，s)，7.12(1H，s)，7.29(2H，d)，7.55(2H，d)，7.64 (1H，t)，7.84(1H，t)，7.88(1H，s)，7.99(1H，d)，8.18 (1H，d)，8.66(1H，s)，8.78(1H，s)，9.55(1H，s)， 12.50(1H，s)
						9578	C 37H 34N 4O 6	MH +631(100％)	ESI	d 6DMSO/400MHz	12.25(1H，s)，10.37(1H，s)，9.32(1H，s)，8.88(1H， s)，8.18-8.08(3H，s)，7.90(1H，t)，7.72(1H，t)，7.62 (2H，d)，7.58(1H，s)，7.24(2H，d)，6.64(1H，s)，6.62 (1H，s)，6.16(2H，s)，3.69(3H，s)，3.68(3H，s)，3.52 (2H，s)，2.82-2.58(8H，m)
9584	C 37H 36N 4O 4	MH +601(100％)	ESI	d 6DMSO/400MHz	11.68(1H，s)，10.44(1H，s)，9.30(1H，s)，8.86(1H，

					s)，8.26(1H，d)，8.16(1H，d)，8.12(1H，d)，7.90(1H， t)，7.74(1H，s)，7.72(1H，t)，7.64(2H，d)，7.46(1H， d)，7.24(2H，d)，6.66(1H，s)，6.64(1H，s)，3.70(3H， s)，3.69(3H，s)，3.68(3H，s)，3.52(2H，s)，2.82-2.76 (2H，m)，2.74-2.62(6H，m)，2.40(3H，s)
						9585	C 35H 32N 4O 4	MH +573(100％)	ESI	d 6DMSO/400MHz	11.74(1H，s)，10.56(1H，s)，9.36(1H，s)，8.90(1H， s)，8.36(1H，d)，8.20-8.06(2H，m)，7.96-7.84(2H， m)，7.78-7.58(4H，m)，7.40-7.28(3H，m)，6.68(1 H， s)，6.60(1H，s)，3.70(3H，s)，3.68(3H，s)，3.60-3.20 (4H，m)，2.82-2.64(4H，m)
9586	C 36H 33ClN 4O 4	MH +621/623 (100％；3∶1)	ESI	d 6DMSO/400MHz	11.99(1H，s)，10.55(1H，s)，9.32(1H，s)，8.89(1H， s)，8.52(1H，s)，8.20-8.06(2H，m)，8.00-7.86(2H， m)，7.73(1H，t)，7.63(2H，d)，7.43(1H，d)，7.25(2H， d)，6.66(1H，s)，6.64(1H，s)，3.70(3H，s)，3.69(3H， s)，3.63(2H，s)2.88-2.66(8H，m)
						9588	C 37H 36N 4O 4	MH +601(100％)	CI +	CDCl 3/400MHz	12.34(1H，s)，9.54(1H，s)，8.80(1H，s)，8.68(1H，s)， 8.22(1H，s)，8.20(1H，d)，8.02(1H，d)，7.84(1H，t)， 7.66(1H，t)，7.62(2H，d)，7.56(1H，d)，7.30(2H，d)， 6.92(1H，d)，6.62(1H，s)，6.56(1H，s)，3.85(3H，s)， 3.84(3H，s)，3.68(2H，s)，2.98-2.74(8H，m)，2.38 (3H，s)
9589	C 36H 35N 5O 4	MH +602(100％)	ESI	d 6DMSO/400MHz	10.12(1H，br.s)，9.80(1H，s)，9.44(1H，s)，9.04(1H，

					s)，8.16-8.08(2H，m)，7.94(1H，s)，7.90(1H，t)，7.78- 7.66(4H，m)，7.20(2H，d)，6.86(1H，d)，6.66(1H，s)， 6.64(1H，s)，5.70(2H，br，d)，3.70(3H，s)，3.69(3H， s)，3.52(2H，s)，2.86-2.52(8H，m)
						9590	C 36H 38N 4O 4 590	MH +591	ESI	d 6DMSO/400MHz	11.65(1H，s)，10.45(1H，s)，8.80(1H，s)，8.38(1H， d)，7.95-7.90(2H，m)，7.67-7.61(3H，m)，7.30(1H， t)，7.27(2H，d)，6.67(1H，s)，6.65(1H，s)，3.82(3H， s)，3.81(3H，s)，3.56(2H，br.s)，2.91-2.70(12H，m)， 1.92-1.88(2H，m)，1.85-1.78(2H，m)
9593	C 35H 33N 4O 4Cl	MH +621(60％) 311(100％)	ESI	CDCl 3/400MHz
						9591	C 36H 33N 4O 4Cl	MH +And 623 (high chlorine isotopes) (100%)-621	ESI	d 6DMSO/400MHz	11.17(s，1H)，10.40(s，1H)，8.70(s，1H)，8.20(d， 1H)，8.07(d，1H)，8.00(d，1H)，7.92(t，1H)，7.82(d， 1H)，7.72(t，1H)，7.60(d，3H)，7.45(t，1H)，7.20(d， 2H)，6.65(s，1H)，6.62(s，1H)，3.70(s，6H)，3.52(s， 2H)，2.80-2.60(m，8H)
9592	C 37H 33N 4O 5F 3	MH +(100％)-671	ESI	d 6DMSO/400MHz	12.50 (s, 1H), 10.35 (s, 1H), 8.95 (s, 1H), 8.42 (d, 1H), 8.35 (d, 1H), 8.20 (s, 1H), 7.70 (d, 1H), 7.65 (d, 2H), 7.58 (d, 1H), 7.59 (t, 1H), 7.23 (d, 2H), 7.22 (t, 1H), 6.65 (s, 1H), 6.60 (s, 1H), 3.70 (s, 6H), 3.55 (s, 2H), and 2.80-2.60 (m, 8H). do not see phenol OH

9594	C 34H 32N 4O 4S	MH +And 208 (100%) (90%)-593	DCI/ NH 3	CDCl 3/400MHz	11.24(s，1H，br)，9.57(d，1H)，8.82(d，1H)，8.45(d， 1H)，8.20(d，1H)，8.02(d，1H)，7.86-7.84(m，1H)， 7.68-7.62(m，1H)7.53(d，2H)，7.51(d，1H)，7.41(s， 1H，br)，7.30(d，2H)，6.61(s，1H)，6.53(s，1H)，3.86 (s，3H)，3.85(s，3H)，3.67(s，2H)，2.95-2.75(m，8H)
						9595	C 38H 39N 5O 4	MH +(100％)-630	ESI	CDCl 3/400MHz	11.48(s，1H)，9.51(s，1H)，8.75(s，1H)，8.60(d，1H)， 8.16(d，1H)，7.98(d，1H)，7.89(s，1H)，7.86-7.80(m， 1H)，7.67-7.62(m，1H)，7.58-7.52(m，2H)7.29(d， 2H)，7.00(s，1H)，6.90(s，1H)，6.61(s，1H)，6.55(s， 1H)，3.87(s，6H)，3.68(s，2H)，3.05(s，6H)，2.98- 2.78(m，8H)
9596	C 37H 38N 6O 4	MH +(100％)-631	ESI	CDCl 3/400MHz	11.83(s，1H)，9.60(s，1H)，8.50(d，1H)，8.25(d， 1H)，8.17(d，1H)，8.00(s，1H)，7.86-7.82(m，2H)， 7.61(d，2H)，7.28(d，2H)，6.95-6.92(m，2H)，6.60 (s，1H)，6.52(s，1H)，3.85(s，6H)，3.62(s，2H)，3.00 (s，6H)，2.95-2.75(m，8H)
						9597	C 33H 31N 5O 4S	MH +(100％)-594	DCI/ NH 3	CDCl 3/400MHz	12.95(s，1H，br)，9.75(s，1H)，8.50(d，1H)，8.40- 8.37(m，1H)8.23-8.20(m，1H)，7.93-7.87(m，2H)， 7.58(d，2H)，7.52(d，1H)，7.42(s，1H，br)，7.32(d， 2H)，6.62(s，1H)，6.55(s，1H)，3.86(s，3H)，3.85(s， 3H)，3.68(s，2H)，3.00-2.79(m，8H)
9600	C 34H 32N 6O 4	MH +(84％)-589	ESI	CDCl 3/400MHz	12.05(s，1H，br)，9.75(s，1H)，8.87-8.47(m，1H)，

		“M 2+”m/2 (100％)-295			8.29(d，1H)8.21(d，1H)，8.04(s，1H，br)，7.94-7.82 (m，3H)，7.71(s，2H，br)，7.29(d，2H)，7.06(s，1H， br)，6.60(s，1H)，6.55(s，1H)，3.84(s，3H)，3.83(s， 3H)，3.69(s，2H)，3.00-2.70(m，8H)
						9606	C 36H 34N 4O 5	MH +(100％)-602.7	CI	d 6-DMSO/400 MHz	12.60(s，1H)，10.35(s，1H)，8.80(s，1H)，8.39(d， 1H)，8.25(d，1H)，7.80-7.45(m，8H)，7.25(m，3H)， 6.65(d，2H)，3.70(s，6H)，3.55(s，2H)，2.85-2.65(m， 8H)
9608	C 34H 33N 5O 4S	MH +(100％)-608	ESI	CDCl 3/400MHz	13.62(s，1H，br)，9.75(s，1H)，8.38-8.34(m，1H)， 8.22-8.18(m，1H)，7.94-7.85(m，2H)，7.72(s，1H， br)，7.61(d，2H)，7.32(d，2H)，6.68(s，1H)，6.62(s， 1H)，6.54(s，1H)，3.85(s，6H)，3.68(s，2H)，2.97- 2.79(m，8H)，2.65(s，3H)
						9609	C 35H 34N 4O 4S	MH +And 304 (80%) (100%)-607	ESI	CDCl 3/400MHz	13.42(s，1H，br)，9.56(d，1H)，8.79(d，1H)，8.19(d， 1H)，8.01(d，1H)，7.85-7.82(m，1H)，7.77(s，1H， br)，7.68-7.62(m，1H)，7.55(d，2H)，7.32(d，2H)， 6.62-6.60(m，2H)，6.53(s，1H)3.84(s，6H)，3.68(s， 2H)，2.96-2.76(m，8H)，2.65(s，3H)
9612	C 34H 33N 5O 4	MH +(100％)-576	ESI	CDCl 3/400MHz	12.67(s，1H)，9.75(s，1H)，8.87(d，1H)，8.34-8.14 (m，2H)7.92-7.82(m，3H)，7.70(d，1H)7.63-7.53 (m，3H)，7.30-7.16(m，3H)，6.90-6.75(m，3H)，3.88 (s，3H)，3.87(s，3H)，3.52(s，2H)，2.92-2.78(m，2H)，

					2.72-2.62(m，2H)，2.30(s，3H)
						9613	C 35H 34N 4O 4	MH +(100％)-575	ESI	CDCl 3/400MHz	12.25(s，1H)，9.55(s，1H)，8.83(d，1H)，8.70(s，1H)， 8.19(d，1H)，8.11(s，1H)，8.02(d，1H)，7.83(t，1H)， 7.70-7.52(m，5H)，7.24(d，2H)，7.16(t，1H)，6.90- 6.78(m，3H)，3.87(s，3H)，3.86(s，3H)，3.50(s，2H)， 2.90-2.80(m，2H)，2.70-2.60(m，2H)，2.21(s，3H)
9614	C 34H 31N 5O 4	MH +(100％)-574	ESI	d 6-DMSO/400 MHz	12.55(s，1H)，10.48(s，1H)，9.59(s，1H)，8.69(d， 1H)，8.22(d，1H)，8.09(d，1H)，8.05-7.95(m，2H)， 7.93(d，1H)，7.64(t，1H)，7.51(d，1H)，7.45(s，H)， 7.30(t，1H)，7.10(d，1H)，6.93(s，1H)，6.90-6.82(m， 2H)，3.74(s，6H)3.60-3.50(m，4H)，2.85-2.64(m， 4H)
						9615	C 37H 36N 4O 4S	MH +And 317 (80%) (100%)-633	ESI	CDCl 3/400MHz	11.95(s，1H，br)，9.46(d，1H)，8.72(d，1H)，8.65(d， 1H)，8.15(s，1H，br)，8.10(d，1H)，7.93(d，1H)， 7.78-7.72(m，1H)，7.58-7.49(m，4H)，7.35(dd，1H)， 7.22(d，2H)，6.55(s，1H)，6.49(s，1H)，3.78(s，6H)， 3.60(s，2H)，2.87-2.68(m，8H)，2.39(s，3H)
9616	C 34H 32N 4O 4S	MH +And 297 (95%) (100%)-593	ESI	CDCl 3/400MHz	11.81(s，1H)，9.47(d，1H)，8.68(d，1H)，8.28(d， 1H)，8.12(d，1H)，7.95(d，1H)，7.85(s，1H，br)， 7.80-7.75(m，2H)，7.60-7.55(m，1H)，7.48(d，2H) 7.28(d，2H)，6.55(s，1H)，6.49(s，1H)，3.78(s，6H)， 3.60(s，6H)，2.87-2.69(m，8H)

9617	C 31H 32N 4O 4S	MH +And 279 (100%) (100%)-557	ESI	CDCl 3/400MHz	11.65(s，1H)，9.16(d，1H)，8.28(d，1H)，8.15(dd， 1H)，7.83-7.80(m，2H)，7.52(d，2H)，7.30-7.28(m， 3H)，6.61(s，1H)，6.55(s，1H)，3.85(s，6H)，3.69(s， 2H)，2.95-2.75(m，8H)，2.65(s，3H)
						9621	C 36H 34N 4O 4S	MH +(60%)-619,310 (50%) and 250 (100%)	ESI	CDCl 3/400MHz	12.12(s，1H，br)，9.55(d，1H)，8.80(d，1H)，8.75(d， 1H)，8.39(s，1H，br)，8.20(d，1H)，8.02(d，1H)， 7.87-7.82(m，1H)，7.69-7.62(m，4H)，7.55-7.50(m， 1H)，7.45(d，2H)，7.10-7.07(m，1H)，6.58(s，1H)， 6.52(s，1H)，3.83(s，3H)，3.81(s，3H)，3.62(s，2H)， 3.20-3.15(m，2H)，2.85-2.75(m，2H)
9622	C 34H 32N 6O 4	MH +And 295 (60%) (100%)-589	ESI	CDCl 3/400MHz	13.18 (s, 1H, br), 10.04 (s, 1H, br), 9.63 (d, 1H), 8.91 (d, 1H), 8.74 (d, 1H), 8.35 (d, 1H), 8.21 (d, 1H), 8.05 (d, 1H), 7.88-7.83 (m, 1H), 7.71-7.65 (m, 3H), 7.32 (m, 2H) 6.61 (s, 1H), 6.55 (s, 1H), 3.85 (2 is unimodal, 6H), and 3.68 (s, 2H), and 2.96-2.78 (m, 8H)
						9623	C 36H 34N 4O 5	MH +(100％)-603	ESI	CDCl 3/400MHz	12.32(s，1H，br)，9.52(s，1H)8.88(d，1H)，8.81(s， 1H)，8.19(d，1H)，8.01(d，1H)，7.90(s，1H，br)， 7.88-7.80(m，1H)，7.72(d，1H)，7.67-7.61(m，2H) 7.56(d，2H)，7.23-7.20(m，1H)6.98(d，2H)，6.60(s， 1H)，6.55(s，1H)，4.24(t，2H)，3.85(s，6H)，3.71(s， 2H)，3.00(t，2H)，2.90-2.88(m，4H)
9625	C 37H 36N 4O 4	MH +(100％)-601	ESI	CDCl 3/400MHz	12.22(s，1H)，9.52(s，1H)，8.84-8.74(m，2H)，8.20-

		(M+2H) 2+，“m 2+“(58％)301			8.10(m，2H)，7.99(d，1H)，7.83(t，1H)，7.72-7.50 (m，5H)，7.32-7.24(m，2H)，7.1 4(t，1H)，6.59(s， 1H)，6.55(s，1H)，3.95-3.75(m，7H)，3.20-3.07(m， 1H)2.95-2.75(m，6H)，2.71-2.59(m，1H)，1.38(d， 3H)
						9626	C 33H 28N 4O 2	MH +(100％)-513.1	ESI	CDCl 3/400MHz	12.25(s，1H)，9.55(s，1H)，8.86(d，1H)，8.80(s，1H)， 8.20(d.1H)，8.04(s，1H)，8.01(d，1H)，7.84(t，1H)， 7.71-7.54(m，5H)，7.32(d，2H)，7.24-7.18(m，5H)， 4.03(s，4H)，3.06-2.97(m，2H)，3.05-2.89 (m.2H)
9628	C 34H 28N 4O 2Cl 2	MH +(100%)-595,597 (50%), 599 (10%) and 475 (90%)	ESI	CDCl 3/400MHz	12.22(s，1H，br)，9.55(d，1H)，8.86-8.81(m，2H)， 8.21-8.15(m，2H)，8.00(d，1H)，7.85-7.81(m，1H)， 7.70-7.52(m，5H)，7.29(d，2H)，7.20(s，1H)，7.18- 7.16(m，1H)，7.12(s，1H)3.64(s，2H)，2.93-2.75(m， 8H)
						9629	C 34H 28N 4O 2Cl 2	MH +(80%)-595,597 (50%), 599 (10%), 399 (70%) and 298 (100%)	ESI	CDCl 3/400MHz	12.25(s，1H，br)，9.55(d，1H)，8.33(d，1H)，8.79(d， 1H)，8.19(d，1H)，8.11(s，1H，br)，8.02(d，1H)， 7.85-7.80(m，1H)，7.70-7.55(m，5H)，7.31(d，2H) 7.25(d，1H)，7.20-7.15(m，1H)6.98(d，1H)，3.85(s， 2H)，2.95-2.75(m，8H)
9630	C 36H 36N 4O 4	MH +(100％)-589	ESI	CDCl 3/400MHz	12.25(s，1H，br)，9.55(d，1H)，8.85(d，1H)，8.80(d， 1H)，8.19(d，1H)，8.11(s，1H，br)，8.02(d，1H)， 7.85-7.80(m，1H)，7.73-7.55(m，5H)，7.25 (d，2H)

					7.20-7.16(m，1H)，6.80-6.72(m，3H)，3.87(s，3H)， 3.85(s，3H)，2.85-2.68(m，8H)，2.39(s，3H)
						9631	C 35H 34N 4O 2	MH +(100％)-543	DCI/ NH 3	CDCl 3/400MHz	12.23(s，1H，br)，9.55(d，1H)，8.81(d，1H)，8.79(s， 1H)，8.19(d，1H)，8.10(s，1H，br)，8.02(d，1H)， 7.85-7.80(m，1H)，7.70-7.58(m，3H)，7.55(d，2H) 7.22(d，2H)，7.1 8-7.12(m，1H)7.08-7.00(m，3H)， 3.52(s，2H)2.86-2.81(m，2H)，2.69-2.62(m，2H)， 2.28(s，3H)，2.25(s，3H)，2.24(s，3H)
9632	C 35H 33N 5O 5	MH +(100％)-604	ESI	CDCl 3/400MHz	12.63(s，1H)，9.68(s，1H)，8.87(d，1H)，8.21(d， 1H)，8.10(d，1H)，7.86(s，1H)，7.80-7.77(m，2H)， 7.60(d，1H)，7.55-7.50(m，3H)，7.1 6-7.11(m，1H)， 6.90(d，2H)，6.53(s，1H)，6.48(s，1H)，4.17(t，2H)， 3.78(s，6H)，3.63(s，2H)，2.97(t，2H)，2.80-2.78(m， 4H)
						9633	C 36H 34N 4O 4	MH +(100％)-587	ESI	CDCl 3/400MHz	12.21(s，1H)，9.53(s，1H)，8.87(d，1H)，8.82(s，1H)， 8.18(d，1H)，8.00(m，2H)，7.85-7.80(m，1H)，7.70 (d，1H)，7.65-7.60(m，2H)，7.50(m，2H)，7.37-7.30 (m，1H)，7.25-7.20(m，1H)，7.11(d，1H)，6.61(s， 1H)，6.55(s，1H)，3.87(s，6H)，3.70(s，2H)，3.00- 2.94(m，2H)2.89-2.82(m，6H)
9634	C 34H 29N 5O 4	MH +(100％)-572	ESI	d 6-DMSO/400Hz	11.78(s，1H，br)，10.48(s，1H，br)，9.33(d，1H)， 8.99(d，1H)，8.39(d，1H)，8.15(d，1H)，8.13(d，1H)，

					7.99(s，1H)，7.97(s，1H)，7.95-7.88(m，2H)，7.85- 7.07(m，6H)，7.71(t，1H)，7.66-7.60(m，3H)，7.40- 7.30(m，2H)，7.24(d，2H)，3.75(s，2H)，2.91(t，2H)
						9635	C 31H 32N 4O 4S	MH +(100％)-557.3	ESI	CDCl 3/400MHz	11.90(s，1H)，8.70(d，1H)，8.05(s，1H)，7.97(s，1H)， 7.65(d，1H)，7.58(d，2H)，7.53(s，1H)，7.25(d，2H )， 7.16(t，1H)，6.62(s，1H)，6.54(s，1H)，3.85(s，6H)， 3.75(s，2H)，3.05-2.83(m，8H)，2.79(s，3H)
9636	C 36H 36N 4O 4	MH +(100％)-589	ESI	CDCl 3/400MHz	12.27(s，1H)，9.55(s，1H)，8.88(d，1H)，8.80(s，1H)， 8.19(d，1H)，8.00(d，1H)，7.95(s，1H，br)，7.88-7.81 (m，1H)，7.70(d，1H)，7.69-7.60(m，2H)7.52(d， 2H)，7.25-7.20(m，3H)6.90(s，1H，br)，6.84-6.78 (m，2H)，3.88(s，6H)，3.60(s，2H，br)，2.82-2.71(m， 4H，br)，2.61(q，2H，br)，1.07(t，3H，br)
						9638	C 31H 32N 4O 5	MH +(100％)-541	ESI	CDCl 3/400MHz	11.69(s，1H)，8.73(d，1H)，8.17(s，1H)，7.87(s，1H)， 7.65(d，1H)，7.60-7.50(m，3H)，7.32-7.23(m，3H)， 7.18(t，1H)6.62(s，1H)，6.55(s，1H)，3.87(s，3H)， 3.86(s，3H)，3.69(s，2H)，3.00-2.74(m，8H)，2.54(s， 3H)
9639	C 37H 38N 4O 4	MH +(100％)-603	ESI	CDCl 3/400MHz	12.20 (s, 1H, br), 9.55 (d, 1H), 8.80-8.75 (m, 2H), 8.35 (s, 1H, br), 8.20 (d, 1H), 8.02 (d, 1H), 7.78-7.72 (m, 1H), and 7.68-7.58 (m, 4H), 7.52 (t, 1H), 7.23 (d, 2H), 7.10 (m, 1H), 6.92 (s, 1H), 6.83 (s, 2H), 4.53 (seven

					Heavy peak, 1H), 3.85 (s, 3H), 3.48 (s, 2H), 2.87-2.81 (m, 2H), 2.68-2.62 (m, 2H), 2.30 (s, 3H), 1.35 (d, 6H.
						9640	C 36H 36N 4O 5	MH +(100％)-605.3	ESI	CDCl 3/400MHz	12.25(s，1H)，9.55(s，1H)，8.85(d，1H)，8.80(s，1H)， 8.20(d，1H)，8.07-8.00(m，2H)，7.84(t，1H)，7.70- 7.53(m，5H)7.30-7.18(m，3H)，6.54(s，2H)3.85(s， 9H)，3.50(s，2H)，2.83(t，2H)，2.66(t，2H)，2.33(s， 3H)
9641	C 38H 40N 4O 4	MH +(100％)-617	ESI	CDCl 3/400MHz	12.25(s，1H)，9.55(d，1H)，8.85(d，1H)，8.80(d， 1H)，8.20(d，1H)，8.05(s，1H，br)，8.02(d，1H)， 7.88-7.81(m，1H)，7.70-7.57(m，3H)，7.53(d，2H)， 7.21-7.15(m，3H)，6.88(s，1H)，6.83-6.78(m，2H) 3.86(s，3H)，3.85(s，3H)，3.58(s，2H)，2.81-2.68(m， 4H)，2.51(t，2H)，1.52-1.47(m，2H)1.35-1.25(m， 2H)，0.90(t，3H)
						9642	C 38H 40N 4O 4	MH +(100％)-617	ESI	CDCl 3/400MHz	12.25(s，1H，br)，9.55(d，1H)，8.85(d，1H)，8.80(d， 1H)，8.19(d，1H)，8.03(s，1H，br)，8.01(d，1H)， 7.85-7.80(m，1H)，7.71-7.58(m，3H)，7.55(d，2H)， 7.22(d，2H)，7.20-7.18(m，1H)，6.85(s，1H)，6.82- 6.78(m，2H)，4.02(t，2H)，3.85(s，3H)，3.50(s，2H)， 2.85(t，2H)，2.65(t，2H)，2.31(s，3H)，1.85-1.79(m， 2H)，1.55-1.45(m，2H)，0.96(t，3H)
9643	C 33H 28N 4O 2F 2	MH +(100％)-551	ESI	CDCl 3/400MHz	12.22(s，1H，br)，9.55(d，1H)，8.81-8.75(m，2H)，

					8.21(s，1H，br)，8.19(d，1H)，8.02(d，1H)，7.85-7.81 (m，1H)，7.68-7.52(m，5H)，7.22(d，2H)，7.17-7.02 (m，3H)，6.97-6.92(m，1H)3.50(s，2H)，2.85(t，2H)， 2.65(t，2H)，2.28(s，3H)
						9645	C 35H 32N 4O 4	MH +(100％)-573	ESI	CDCl 3/400MHz	12.18(s，1H，br)，9.50(s，1H)，8.78(d，1H)，8.72(s， 1H)，8.11(d，1H)，7.95(d，1H)，7.92(s，1H)，7.78- 7.72(m，1H)，7.62-7.50(m，5H)，7.18-7.10(m，3H)， 6.75-6.70(m，3H )，4.18(s，4H)，3.40(s，2H)，2.78(t， 2H)，2.58(t，2H)，2.20(s，3H)
9646	C 37H 38N 4O 4	MH +(100％)-603	ESI	CDCl 3/400MHz	12.15(s，1H，br)，9.45(s，1H)，8.72(s，1H)，8.70(d， 1H)，8.25(s，1H)，8.11(d，1H)，7.90(d，1H)，7.78- 7.72(m，1H)，7.60-4.41(m，5H)，7.13(d，2H)，7.04- 7.00(m，1H)，6.79-6.68(m，3H)，4.45-4.39(m，1H)， 3.78(s，3H)，3.40(s，2H)，2.78-2.72(m，2H)，2.60- 2.56(m，2H)，2.23(s，3H)，1.30(s，3H)，1.28(s，3H)
						9647	C 34H 32N 4O 4	MH +(100％)-561	ESI	CDCl 3/400MHz	12.23 (s, 1H, br), 9.54 (s, 1H), 8.88 (d, 1H), 8.82 (s, 1H), 8.19 (d, 1H), 8.10 (s, 1H, br), 8.00 (d, 1H), 7.85-7.80 (m, 1H), 7.70 (d, 1H), 7.65-7.55 (m, 4H), 7.22 (d, 2H), 7.20-7.15 (m, 1H) 6.88 (s, 1H), 6.80-6.78 (m, 2H) 3.88 (s, 3H), 3.50 (s, 2H), 2.85 (t, 2H), 2.65 (t, 2H), 2.29 (s, 3H) the .OH proton does not observe
9648	C 37H 36N 4O 6	MH +(40％)-633	ESI	CDCl 3/400MHz	12.29(s，1H)，9.55(s，1H)，8.87(d，1H)，8.81(s，1H)，

		“M 2+”317 (100％)			8.18 (d, 1H), 8.02-7.96 (m, 2H), and 7.85-7.80 (m, 1H), 7.72-7.50 (m, 5H), 7.26-7.18 (m, 1H), 6.98 (d, 2H), 6.61 (s, 1H), 6.54 (s, 1H), and 4.31-4.24 (m, 1H), 4.10 (d, 2H), 3.87 (s, 3H), 3.86 (s, 3H), 3.82 (d, 1H), 3.64 ((d, 1H), (m, 6H) the OH proton does not observe 3.04-2.72
						9649	C 34H 32N 4O 4	MH +(50％)-425	ESI	CDCl 3/400MHz	12.25 (s.1H), 9.55 (d, 1H), 8.82 (d, 1H), 8.75 (d, 1H), 8.43 (s, 1H), 8.22 (d, 1H), 7.98 (d, 1H), 7.81 (t, 1H), 7.67-7.54 (m, 4H), 7.50-7.43 (m, 1H), 7.29 (d, 2H), 7.07 (t, 1H), 6.88-6.81 (m, 2H), and 6.73-6.68 (m, 1H), 3.82 (s, 3H), 3.50 (s, 2H), 2.89-2.82 (m, 2H), and 2.70-2.63 (m, 2H), 2.34 (s, 3H) the OH proton does not observe
9650	C 37H 36N 4O 4	MH +(100％)-601 “M 2+”301 (86％)	ESI	CDCl 3/400MHz	12.33(s，1H)，9.53(s，1H)，8.90(d，1H)，8.77(s，1H)， 8.17(d，1H)，7.99(d，1H)，7.88-7.58(m，6H)，7.30- 7.12(m，3H)6.62(s，1H)，6.55(s，1H)，3.85(s，3H)， 3.84(s，3H)，3.70(s，2H)，3.00-2.75(m，8H)，2.35(s， 3H)
						9651	C 37H 36N 4O 5	MH +(100％)-617 “M 2+”309 (58％)	ESI	CDCl 3/400MHz	12.48(s，1H)，9.57(s，1H)，8.91(d，1H)，8.84(s，1H)， 8.61(s，1H)，8.39(d，1H)，8.19(d，1H)，8.02(d，1H)， 7.84(t，1H)，7.73(d，1H)，7.65-7.60(m，2H)7.30- 7.20(m，1H)，7.03(d，1H)6.85(s，1H)，6.61(s，1H)，

					6.55(s，1H)，3.92(s，3H)，3.87(s，3H)，3.86(s，3H)， 3.70(s，2H)，3.00-2.70(m，8H)
						9652	C 36H 36N 4O 4	MH +(100％)-589	ESI	CDCl 3/400MHz	12.18 (s, 1H, br), 9.55 (d, 1H), 8.80 (d, 1H), 8.75 (d, 1H), 8.39 (s, 1H, br), 8.20 (d, 1H), 8.02 (d, 1H), (7.86-7.82 m, 1 H), 7.68-7.62 (m, 4 H), 7.52-7.49 (m, 1H), 7.41 (d, 2H), 7.10-7.05 (m, 1H), 6.98 (d, 1H), and 6.91-6.83 (m, 2H), (4.55 septet, 1 H), 3.83 (s, 3H), 3.51 (s, 2H), 3.48 (s, 2H), 2.20 (s, 3H), 1.36 (d, 6H)
9653	C 32H 33N 5O 4	MH +(100％)-552	ESI	CDCl 3/400MHz	12.33(s，1H)，9.31(s，1H)，8.78(d，1H)，8.50(s，1H)， 8.00(s，1H)，7.65(d，1H)，7.61(t，1H)，7.55-7.46(m， 2H)，7.32(t，1H)，7.20(t，1H )，7.08(d，1H)，6.52(s， 1H)，6.45(s，1H)，3.79(s，6H)，3.60(s，2H)，2.92- 2.88(m，2H)，2.80-2.70(m，6H)，2.65(s，3H )
						9654	C 37H 36N 4O 4	MH +(100％)-601	ESI	d 6-DMSO/400 MHz	11.80(s，1H)，10.47(s，1H)，9.34(s，1H)，8.88(s， 1H)，8.38(d，1H)，8.17-8.07(m，2H)，7.94-7.87(m， 2H)，7.72(t，1H)，7.66-7.60(m，3H)，7.34(t，1H)， 7.23(d，2H)，6.63(s，1H)，6.59(s，1H)，3.68(s，6H)， 3.55-3.35(m，2H)，3.08-2.95(m，1H)，2.70-2.40(m， 6H)，1.19(d，3H)
9655	C 35H 35N 5O 2	MH +(100％)-558	ESI	CDCl 3/400MHz	10.26(s，1H，br)，9.53(d，1H)，8.85(d，1H)，8.80(d， 1H)，8.20(d，1H)，8.10(s，1H)，8.00(d，1H)，7.82(t， 1H)，7.70(d，1H)，7.68-7.52(m，3H)，7.55(d，2H)

					7.38-7.29(m，4H)，6.80(d，2H)3.62(s，2H，br)，2.94 (s，6H)，2.93-2.90(m，2H，br)，2.80-2.74(m，2H，br)， 2.36(s，3H，br)
						9656	C 40H 44N 4O 6	MH +(100％)-677	ESI	CDCl 3/400MHz	12.45(s，1H)，9.50(s，1H)，8.71(s，1H)，8.54(s，1H)， 8.50(s，1H)，8.15(d，1H)，7.98(d，1H)，7.81-7.79 (m，1H)，7.60-7.55(m，3H)，7.20(d，2H)，7.10(s， 1 H)，6.85(s，1H)，6.78(s，2H)，3.97(t，2H)，3.88(s， 3H)，3.81(s，3H)，3.68(s，3H)，3.47(s，2H)，2.80(t， 2H)，2.62(t，2H)，2.28(s，3H)，1.81-1.75(m，2H)， 1.50-1.42(m，2H)，0.92(t，3H)
9657	C 33H 35N 5O 5	MH +(100％)-582	ESI	d 6-DMSO/400 MHz	12.65(s，1H，br)，9.93(s，1H)，9.35(s，1H)，8.89-8.78 (m，2H)7.94(d，1H)，7.76(t，1H)，7.48(d，1H)，7.58 (t，1H)，7.05(s，1H)，6.77(d，1H)，6.45(s，1H)，6.30 (s，1H)，3.63(s，3H)，3.71(s，3H)，3.70(s，3H)，3.58 (s，2H，br)，2.89-2.83(m，2H)，2.70(m，6H)，2.59(s， 3H)
						9658	C 32H 33N 5O 4	MH +(100％)-568	ESI	d 6-DMSO/400 MHz	12.62(s，1H，br)，9.27(s，1)，9.32(s，1H)，8.90(m， 1H)，8.80(m，1H)，8.71(s，1H)，8.70(s，1H)，7.97 (d，1H)，7.65(t，1H)，7.47(d，1H)，7.30(t，1H)，7.02 (s，1H)，6.68(d，1H)，6.67(s，1H)，6.65(s，1H)，3.77 (s，3H)，3.70(s，3H)，3.69(s，3H)，3.56(s，2H)，2.87- 2.82(m，2H)，2.75-2.68(m，6H)

9659	C 32H 33N 5O 5	MH +(100％)-552	ESI	d 6-DMSO/400 MHz	10.15(s，1H)，9.34(s，1H)，8.90(d，1H)，8.80-8.77 (m，1H)8.74(d，1H)，8.02(d，1H)，7.65(t，1H)，7.33 (t，1H)，7.23-7.17(m，2H)，7.15-7.08(m，1H)6.66 (s，1H)，6.64(s，1H)，3.655(s，3H)，3.65(s，3H)，3.57 (s，2H)，2.85-2.78(m，2H)，2.75-2.26(m，6H)，2.21 (s，3H)
						9600	C 37H 36N 4O 4	MH +(100％)-601	ESI	CDCl 3/400MHz	12.16(s，1H)，9.48(d，1H)，8.76-8.72(m，2H)，8.12- 8.07(m，2H)，7.92(d，1H)，7.86-7.50(m，1H)，7.63- 7.44(m，4H)7.40(s，1H)，7.28-7.23(m，1H)，7.11- 7.04(m，1H)，7.00(d，1H)，6.49(s，1H)，6.43(s，1H)， 3.76(s，3H)，3.72(s，3H)，3.48(s，2H)，2.76-2.61(m， 6H)，2.50-2.44(m，2H)，1.94-1.84(m，2H)
9661	C 32H 34N 4O 4	MH +(100％)-539.4	DCI +/ NH 3	CDCl 3/400MHz	12.01 (s, 1H), 9.27 (s, 1H), and 8.81-8.76 (m, 1H), 8.71 (d, 1H) 8.34-8.26 (m, 2H), 7.67-7.58 (m, 3H), 7.52-7.37 (m, 4H), and 7.11-7.03 (m, 1H), 6.98 (d, 1H) 6.89-6.82 (m, 2H), 4.55 (septet, 1H), 3.85 (s, 3H), 3.50 (s, 2H), 3.48 (s, 2H), 2.21 (s, 3H), 1.38 (d, 6H)
						9663	C 35H 33N 4O 4Cl	MH +(62％)-609 M +Na +(100％)-631	ESI	d 6-DMSO/400 MHz	12.00(s，1H)，9.34(s，1H)，8.89(s，1H)，8.54(s，1H)， 8.18-8.08(m，2H)，7.97(d，1H)，7.91(t，1H)，7.71 (t，1H)，7.61(d，2H)，7.42(d，1H)，7.19(d，2H)， 6.86-6.78(m，2H)，6.77-6.71(m，1H)，3.70(s，3H)， 3.68(s，3H)，3.43(s，2H)，2.78-2.70(m，2H)，2.59-

					2.52(m，2H)2.17(s，3H)
						9664	C 35H 30N 4O 4	MH +(100％)-571	ESI	d 6-DMSO/400 MHz	11.80(s，1H)，10.46(s，1H)，9.33(s，1H)，8.89(s， 1H)，8.38(d，2H)，8.18-8.08(m，2H)，7.95-7.87(m， 2H)，7.72(t，1H)，7.67-7.60(m，3H)，7.34(t，1H)， 7.22(d，2H)，6.62(s，1H)，6.60(s，1H)，5.90(s，2H)， 3.50(s，2H)，2.83-2.75(m，2H)，2.72-2.60(m，6H)
9665	C 38H 38N 4O 4	MH +(100％)-615	ESI	d 6-DMSO/400 MHz	11.80(s，1H)，10.46(s，1H)，9.33(s，1H)，8.88(s， 1H)，8.38(d，1H)，8.17-8.07(m，2H)，7.97-7.87(m， 2H)，7.71(t，1H)7.67-7.58(m，3H)，7.32(t，1H)7.22 (d，2H)，6.62(s，1H)，6.60(s，1H)，3.83(q，4H)，3.50 (s，2H)，2.82-2.74(m，2H)，2.72-2.60(m，6H)，1.27 (t，6H)
						9666	C 36H 32N 6O 4S	MH +(60％)-645	ESI	CDCl 3/400MHz	9.75(s，1H br)，9.55(d，1H)，9.27(s，1H，br)，8.90 (d，1H)，8.73(d，1H)，8.63(d，1H)，8.21(d，1H)， 8.00(d，1H)，7.90-7.85(m，1H)，7.71-7.66(m，1H) 7.55(d，2H)，7.21(d，2H)，6.55(s，1H)，6.50(s，1H)， 3.83(s，3H)，3.82(s，3H)，3.62(s，2H)，2.90-2.70(m， 8H)
9667	C 35H 32N 4O 4F 2	MH +(100％)-611.5	DCI +/ NH 3	CDCl 3/400MHz	12.35(s，1H)，9.51(s，1H)，8.93-8.88(m，1H)，8.78 (s，1H)，8.20(d，1H)，8.00(d，1H)，7.83(t，1H)，7.78 (s，1H)，7.64(t，1H)，7.56-7.49(m，3H)，7.23(d， 2H)，6.88(s，1H)，6.80(s，2H)，3.88(s，6H)，3.50(s，

					2H)，2.86-2.80(m，2H)，2.68-3.63(m，2H)，2.31(s， 3H)
						9668	C 36H 36N 4O 4	MH +(100％)-589	ESI	CDCl 3/400MHz	12.32(s，1H)，9.55(d，1H)，8.78(d，1H)，8.65(s， 1H)，8.21(s，1H)，8.19(d，1H)，8.02(d，1H)，7.85(t， 1H)，7.65(t，1H)，7.60(d，2H)，7.55(d，1H)，7.23(d， 2H)，6.90(d，1H)，6.89(s，1H)，6.85-6.80(m，2H)， 3.86(s，6H)，3.50(s，2H)，2.85-2.8 1(m，2H)，2.70- 2.65(m，2H)2.35(s，3H)，2.28(s，3H)
9669	C 37H 38N 4O 4	MH +(100％)-603	ESI	CDCl 3/400MHz	12.20 (s, 1H), 9.53 (d, 1H), 8.80 (d, 1H), 8.75 (d, 1H), 8.35 (s, 1H), 8.19 (d, 1H), 8.01 (d, 1H), 7.85-7.81 (m, 1H), 7.65-7.60 (m, 2H), 7.55 (d, 2H), 7.48 (t, 1H), 7.17 (d, 2H), 7.05 (t, 1H), 6.91 (s, 1H), and 6.85-6.75 (m, 2H), 3.86 (s, 3H), 3.85 (s, 3H), 3.59 (s, 2H), 2.99 (septet, 1H), 2.69 (s, 4H), 1.00 (d, 6H)
						9677	C 35H 33N 5O 6	MH +(35％)-620	ESI	d 6-DMSO/400 MHz	11.72(s，1H)，10.72(s，1H)，9.35(s，1H)，9.14(s， 1H)，8.90(s，1H)，8.24-8.06(m，4H)，7.94(t，1H)， 7.72(t，1H)，7.65(d，2H)，7.20(d，2H)，6.88-6.70(m， 3H)，3.69(s，3H)，3.68(s，3H)，3.44(s，2H)，2.78- 2.68(m，2H)，2.62-2.50(m，2H)2.17(s，3H)

Claims (14)

1. compound, it is the anthranilic acid derivative of formula (I), or its pharmacy acceptable salt:

Wherein

R, R ¹And R ², can be identical or different, H, C respectively do for oneself ₁-C ₆Alkyl, OH, C ₁-C ₆Alkoxyl group, halogen, nitro or N (R ¹⁰R ¹¹) R wherein ¹⁰And R ¹¹Can be identical or different, H or C respectively do for oneself ₁-C ₆Alkyl, or R ¹And R ²Be connected common methylene-dioxy or the ethylenedioxy of forming on the close position that encircles b;

R ³Be H or C ₁-C ₆Alkyl;

R ⁴Be C ₁-C ₆Alkyl or R ⁴Representative-CH ₂-or-CH ₂CH ₂-, it or link to each other with (i) ring 2 of b form one with ring b thick and saturated 5-or 6-unit contain azo-cycle, or with (ii) encircle a go up position that the ortho position is connected with singly-bound X link to each other one of formation with encircle a thick and saturated 5-or 6-unit contain azo-cycle;

R ⁵Be H, OH or C ₁-C ₆Alkyl;

X be direct key, O, S ,-S-(CH ₂) _p-or-O-(CH ₂) _p-, wherein p is the integer of 1-6;

R ⁶Be H, C ₁-C ₆Alkyl or C ₁-C ₆Alkoxyl group;

Q is 0 or 1;

Ar is undersaturated carbocyclic ring or heterocycle, wherein undersaturated heterocyclic group be selected from furans, thiophene, pyrroles, indoles, isoindole, pyrazoles, imidazoles, different _ azoles, _ azoles, isothiazole, thiazole, pyridine, quinoline, quinoxaline, isoquinoline 99.9, thieno-pyrazine, pyrans, pyrimidine, pyridazine, pyrazine, purine and triazine group, it is not replace or be selected from OH, halogen, C by one or more ₁-C ₆Alkoxyl group, nitro, amino group N (R as defined above ¹⁰R ¹¹) and the C that do not replace or replaced by halogen ₁-C ₆The substituting group of alkyl replaces;

R ⁷And R ⁸Can be identical or different, the H that respectively does for oneself, do not replace or by 1,23 C that halogen atom replaces ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, hydroxyl, halogen, phenyl ,-NHOH, nitro, N (R as defined above ¹⁰R ¹¹) or SR ¹²R wherein ¹²Be H or C ₁-C ₆Alkyl; Or R ⁷And R ⁸, when they were positioned on the adjacent carbons, the carbon atom that links to each other with them formed phenyl ring or methylene-dioxy substituting group;

R ⁹Be phenyl or undersaturated heterocycle,, wherein undersaturated heterocyclic group be selected from furans, thiophene, pyrroles, indoles, isoindole, pyrazoles, imidazoles, different _ azoles, _ azoles, isothiazole, thiazole, pyridine, quinoline, quinoxaline, isoquinoline 99.9, thieno-pyrazine, pyrans, pyrimidine, pyridazine, pyrazine, purine and triazine group; Any one all is not replace or by C ₁-C ₆Alkyl, OH, C ₁-C ₆Alkoxyl group, halogen, C ₃-C ₆Cycloalkyl, phenyl, benzyl, trifluoromethyl, nitro, ethanoyl, benzoyl or N (R as defined above ¹⁰R ¹¹) replace, or locational two substituting groups of the adjacent ring of this phenyl or heterocyclic group form a saturated or undersaturated 6-unit ring together, or form methylene-dioxy;

N is 0 or 1;

M is 0 or the integer of 1-6.

2. according to the compound of claim 1, wherein said anthranilic acid derivative has following structure (A):

Wherein

(a) R, R ¹And R ², can be identical or different, H, OH, NO respectively do for oneself ₂, N (R ¹⁰R ¹¹), halogen or C ₂-C ₆Alkoxyl group or R are H, R ¹And R ²The carbon atom that links to each other with them forms methylene-dioxy or ethylenedioxy, and condition is R, R ¹And R ²Not all be H; R ³, R ⁵, R ⁶, R ⁷, R ⁸, R ⁹, Ar, X and m each freely claim 1 define; Or

(b) R, R ¹And R ², can be identical or different, respectively do for oneself H or OMe, R ³, R ⁵, R ⁶, R ⁷, R ⁸, R ⁹, Ar, X and m each freely claim 1 define.

3. according to the compound of claim 1, wherein said anthranilic acid derivative has following structure (B):

Wherein R, R ¹-R ³, R ⁵-R ⁹, Ar and n such as claim 1 definition.

4. according to the compound of claim 1, wherein said anthranilic acid derivative has following structure (C):

Wherein R, R ¹-R ³, R ⁵-R ⁹, Ar, X and m such as claim 1 definition.

5. according to the compound of claim 1, wherein said anthranilic acid derivative has following structure (D):

Wherein R, R ¹-R ⁹, Ar, m and n such as claim 1 definition, X on 3 or 4 of ring a, its such as claim 1 definition.

6. according to the compound of claim 1, it is anthranilic acid derivative or its pharmacy acceptable salt of formula (Ia):

R wherein ¹¹And R ²¹Can be identical or different, be respectively hydrogen or methoxyl group; R ³¹And R ⁴¹Can be identical or different, independently be selected from H, CH separately ₃, CF ₃, F, Cl, Br, NH ₂, NO ₂, NHOH, methoxyl group, hydroxyl and phenyl; Or R ³¹And R ⁴¹When being positioned on the adjacent carbon atom, they form phenyl ring or methylene-dioxy substituting group with the carbon atom that links to each other; R ⁵¹Ring one of among 2-furyl, 3-furyl, 2-thiophene, 3-thiophene, 2-indyl or 2-benzofuryl or following formula (II '), (III ') or (IV '):

R wherein ⁶¹And R ⁷¹Can be identical or different, be selected from the C of hydrogen, linearity or side chain ₁-C ₆Alkyl, C ₃-C ₆Cycloalkyl, phenyl, benzyl, trifluoromethyl, F, Cl, Br, OR ¹², NO ₂, dimethylamino, diethylin, ethanoyl and benzoyl, or R ⁶¹And R ⁷¹When being positioned on the adjacent carbon atom, they form phenyl ring or methylene-dioxy substituting group with the carbon atom that links to each other;

R ⁸¹And R ⁹¹Can be identical or different, respectively do for oneself hydrogen, methyl or methoxy, or R ⁸¹And R ⁹¹When being positioned on the adjacent carbon atom, they form quinoline or 5,6,7,8-tetrahydroquinoline ring system with the pyridine that links to each other;

R ¹⁰¹And R ¹¹¹Can be identical or different, respectively do for oneself hydrogen, methyl or propionyl; Or R ¹⁰¹And R ¹¹¹When being positioned on the adjacent carbon atom, they form phenyl ring with the carbon atom that links to each other;

R ¹²¹Be H, C ₁-C ₆Alkyl, C ₃-C ₆Cycloalkyl, phenyl, benzyl or ethanoyl;

R is 0 or 1;

S is 1,2 or 3.

7. according to the compound of claim 6, wherein in formula (Ia), r is 1, and s is 2, R ¹¹And R ²¹All be methoxyl group, R ⁵¹Be 2-quinoxaline, 3-quinoline, 2-pyrazine or 3-pyridine group, all these groups all can not replace or replace:

8. according to the compound of claim 1, it is following compound or its pharmacy acceptable salt:

2-chloro-quinoline-3-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides

4-hydroxyl-7-fluoroform yl-quinoline-3-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides

Quinoline-3-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-thiene-3-yl-)-acid amides

Quinoline-3-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-4-dimethylamino-phenyl)-acid amides

Quinoxaline-2-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-4-dimethylamino-phenyl)-acid amides

Quinoxaline-2-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-thiene-3-yl-)-acid amides

Quinoxaline-2-formic acid (3-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-pyridine-2-yl)-acid amides

4-hydroxyl-quinoline-3-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides

Quinoxaline-2-formic acid (3-{4-[2-(6,7-dimethoxy-3,4-hydrogen-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-4-methyl-thiophene-2-yl)-acid amides

Quinoline-3-formic acid (3-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-4-methyl-thiophene-2-yl)-acid amides

Quinoxaline-2-formic acid [2-(4-{2-[(3,4-dimethoxy-benzyl)-methyl-amino]-ethyl }-the phenyl amino formyl radical)-phenyl]-acid amides

Quinoline-3-formic acid [2-(4-{2-[(3,4-dimethoxy-benzyl)-methyl-amino]-ethyl }-the phenyl amino formyl radical)-phenyl]-acid amides

Quinoxaline-2-formic acid 2-[2-(3,4-dimethoxy-benzyl)-1,2,3,4-tetrahydroisoquinoline-7-base formamyl]-phenyl }-acid amides

Quinoline-3-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-4-first sulphur alkyl-phenyl)-acid amides

Quinoline-3-formic acid (4-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-thiene-3-yl-)-acid amides

N-(4-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-thiene-3-yl-)-6-methyl-niacinamide

Quinoline-3-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-second sulfane base]-the phenyl amino formyl radical }-phenyl)-acid amides

Quinoline-3-formic acid (3-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-pyrazine-2-yl)-acid amides

Quinoline-3-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-oxyethyl group]-the phenyl amino formyl radical }-phenyl)-acid amides

Quinoline-3-formic acid (2-{4-[2-(6,7-dimethoxy-1-methyl-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides

Quinoline-3-formic acid (2-{4-[2-(1,3-dihydro-isoindole-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides

Quinoline-3-formic acid (2-{4-[2-(6,7-two chloro-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides

Quinoline-3-formic acid (2-{4-[2-(7,8-two chloro-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides

Quinoline-3-formic acid 2-[4-(2-{[2-(3,4-dimethoxy-phenyl)-ethyl]-methyl-amino }-ethyl)-the phenyl amino formyl radical]-phenyl }-acid amides

Quinoline-3-formic acid [2-(4-{[2-[(3,4-dimethyl-benzyl)-methyl-amino]-ethyl }-the phenyl amino formyl radical)-phenyl]-acid amides

Quinoxaline-2-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-oxyethyl group]-the phenyl amino formyl radical }-phenyl)-acid amides

Quinoline-3-formic acid (2-{3-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides

Quinoline-3-formic acid (2-{4-[2-(7-nitro-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides

2-methyl-thiazole-4-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides

Quinoline-3-formic acid [2-(4-{2-[(3,4-dimethoxy-benzyl)-ethyl-amino]-ethyl }-the phenyl amino formyl radical)-phenyl]-acid amides

The 2-methyl-_ azoles-4-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides

Quinoline-3-formic acid [2-(4-{2-[(3-isopropoxy-4-methoxyl group-benzyl)-methyl-amino]-ethyl }-the phenyl amino formyl radical)-phenyl]-acid amides

Quinoline-3-formic acid [2-(4-{2-[methyl-(3,4,5-trimethoxy-benzyl)-amino]-ethyl }-the phenyl amino formyl radical)-phenyl]-acid amides

Quinoline-3-formic acid [2-(4-{2-[butyl-(3,4-dimethoxy-benzyl)-amino]-ethyl }-the phenyl amino formyl radical)-phenyl]-acid amides

Quinoline-3-formic acid [2-(4-{2-[(4-butoxy-3-methoxyl group-benzyl)-methyl-amino]-ethyl }-the phenyl amino formyl radical)-phenyl]-acid amides

Quinoline-3-formic acid [2-(4-{2-[(3,4-two fluoro-benzyls)-methyl-amino]-ethyl }-the phenyl amino formyl radical)-phenyl]-acid amides

Quinoline-3-formic acid [2-(4-{2-[(2,3-dihydro-benzo [1,4] two oxines-6-ylmethyl)-methyl-amino]-ethyl }-the phenyl amino formyl radical)-phenyl]-acid amides

Quinoline-3-formic acid [2-(4-{2-[(4-isopropoxy-3-methoxyl group-benzyl)-methyl-amino]-ethyl }-the phenyl amino formyl radical)-phenyl]-acid amides

Quinoline-3-formic acid [2-(4-{2-[(3-hydroxyl-4-methoxyl group-benzyl)-methyl-amino]-ethyl }-the phenyl amino formyl radical)-phenyl]-acid amides

Quinoline-3-formic acid [2-(4-{3-[(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-2-hydroxyl-propoxy-]-phenyl amino formyl radical }-phenyl)-acid amides

Quinoline-3-formic acid [2-(4-{2-[(4-hydroxyl-3-methoxyl group-benzyl)-methyl-amino]-ethyl }-the phenyl amino formyl radical)-phenyl]-acid amides

Quinoline-3-formic acid [2-(4-{2-[(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-2-methyl-phenyl amino formyl radical }-phenyl)-acid amides

Quinoline-3-formic acid [2-(4-{2-[(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-2-methoxyl group-phenyl amino formyl radical }-phenyl)-acid amides

Quinoline-3-formic acid [2-(4-{[(3-isopropoxy-4-methoxyl group-benzyl)-methyl-amino]-methyl }-the phenyl amino formyl radical)-phenyl]-acid amides

5-methyl-pyrazine-2-formic acid (2-{3-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides

Quinoline-3-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-1-methyl-ethyl]-2-phenyl amino formyl radical }-phenyl)-acid amides

Quinoline-3-formic acid [2-(4-{2-[(4-dimethylamino-benzyl)-methyl-amino]-ethyl }-the phenyl amino formyl radical)-phenyl]-acid amides

Quinoline-3-formic acid [2-(4-{2-[(3-butoxy-4-methoxyl group-benzyl)-methyl-amino]-ethyl }-the phenyl amino formyl radical)-4,5 dimethoxys-phenyl]-acid amides

5-methyl-pyrazine-2-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-2-methoxyl group-phenyl amino formyl radical }-phenyl)-acid amides

Pyrazine-2-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-2-methyl-phenyl amino formyl radical }-phenyl)-acid amides

Pyrazine-2-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-2-methoxyl group-phenyl amino formyl radical }-phenyl)-acid amides

Quinoline-3-formic acid (2-{3-[3-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-propyl group]-the phenyl amino formyl radical }-phenyl)-acid amides

N-[2-(4-{[(3-isopropoxy-4-methoxyl group-benzyl)-methyl-amino]-methyl }-the phenyl amino formyl radical)-phenyl]-niacinamide

Quinoline-3-formic acid [5-chloro-2-(4-{2-[(3,4-dimethoxy-benzyl)-methyl-amino]-ethyl }-the phenyl amino formyl radical)-phenyl]-acid amides

Quinoline-3-formic acid (2-{4-[2-(7,8-dihydro-5H-[1,3] dioxole also [4,5-g] isoquinoline 99.9-6-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides

Quinoline-3-formic acid (2-{4-[2-(6,7-diethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides

Quinoline-3-formic acid (6-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-thieno-[2,3-b] pyrazine-7-yl)-acid amides

Quinoline-3-formic acid [2-(4-{2-[(3,4-dimethoxy-benzyl)-methyl-amino]-ethyl }-the phenyl amino formyl radical)-4,5-two fluoro-phenyl]-acid amides

Quinoline-3-formic acid [2-(4-{2-[(3,4-dimethoxy-benzyl)-methyl-amino]-ethyl }-the phenyl amino formyl radical)-5-methyl-phenyl]-acid amides

Quinoline-3-formic acid [2-(4-{2-[(3,4-dimethoxy-benzyl)-sec.-propyl-amino]-ethyl }-the phenyl amino formyl radical)-phenyl]-acid amides

Quinoline-3-formic acid [2-(4-{2-[(3,4-dimethoxy-benzyl)-methyl-amino]-ethyl }-the phenyl amino formyl radical)-5-nitro-phenyl]-acid amides

2-(4-sec.-propyl-benzamido)-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-benzamide

2-(4-sec.-propyl-benzamido)-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-6-chloro-benzamide

2-(4-sec.-propyl-benzamido)-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-5-chloro-benzamide

2-(4-sec.-propyl-benzamido)-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-4-chloro-benzamide

2-(4-sec.-propyl-benzamido)-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-3-chloro-benzamide

2-(4-sec.-propyl-benzamido)-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-5-bromo-benzamide

2-(4-sec.-propyl-benzamido)-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-4-fluoro-benzamide

2-(4-sec.-propyl-benzamido)-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-3-methyl-benzamide

2-(4-sec.-propyl-benzamido)-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-3-methoxyl group-benzamide

2-(4-sec.-propyl-benzamido)-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-3-hydroxyl-benzamide

(2-(4-sec.-propyl-benzamido)-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-4-nitro-benzamide

2-(4-sec.-propyl-benzamido)-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-4-amino-benzamide

2-(4-sec.-propyl-benzamido)-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-5-phenyl-benzamide

3-(4-sec.-propyl-benzamido)-naphthalene-2-formic acid [2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl] acid amides

2-(4-dimethylamino-benzamido)-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-benzamide

2-(4-propyl group-benzamido)-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-benzamide

2-(4-amyl group-benzamido)-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-benzamide

2-(4-cyclohexyl-benzamido)-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-benzamide

Xenyl-4-formic acid 2-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethylamino formyl radical]-phenyl }-acid amides

Naphthalene-2-formic acid 2-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethylamino formyl radical]-phenyl }-acid amides

Benzo [1,3] dioxole-5-formic acid 2-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethylamino formyl radical]-phenyl }-acid amides

2-(4-diethylin-benzamido)-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-benzamide

2-(the 4-tertiary butyl-benzamido)-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-benzamide

2-benzamido-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-benzamide

2-(4-bromo-benzamido)-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-benzamide

2-(4-nitro-benzamido)-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-benzamide

2-(4-phenoxy group-benzamido)-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-benzamide

2-(4-benzoyl-benzamido)-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-benzamide

2-(4-benzyl-benzamido)-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-benzamide

2-(4-cyclohexyloxy-benzamido)-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-benzamide

2-(4-benzyloxy-benzamido)-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-benzamide

Pyridine-2-formic acid 2-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethylamino formyl radical]-phenyl }-acid amides

N-{2-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethylamino formyl radical]-phenyl }-niacinamide

N-{2-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethylamino formyl radical]-phenyl }-Isonicotinamide

Pyrazine-2-formic acid 2-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethylamino formyl radical]-phenyl }-acid amides

Quinoxaline-2-formic acid 2-[2-(6,7-methoxyl group-3,4-hydrogen-1H-isoquinoline 99.9-2-yl)-ethylamino formyl radical]-phenyl }-acid amides

Isoquinoline 99.9-1-formic acid 2-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethylamino formyl radical]-phenyl }-acid amides

Quinoline-2-formic acid 2-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethylamino formyl radical]-phenyl }-acid amides

Isoquinoline-3-carboxylic acid 2-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethylamino formyl radical]-phenyl }-acid amides

Quinoline-3-formic acid 2-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethylamino formyl radical]-phenyl }-acid amides

Thiophene-3-formic acid 2-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethylamino formyl radical]-phenyl }-acid amides

The 1H-indole-2-carboxylic acid 2-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethylamino formyl radical]-phenyl }-acid amides

Quinoxaline-2-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides

Quinoxaline-2-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-5-hydroxylamino-phenyl)-acid amides

Quinoxaline-2-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-4-methyl-phenyl)-acid amides

Quinoxaline-2-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-4-hydroxyl-phenyl) acid amides

Quinoxaline-2-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-5-nitro-phenyl)-acid amides

Quinoxaline-2-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-5-trifluoromethyl-phenyl)-acid amides

Quinoxaline-2-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-5-fluoro-phenyl)-acid amides

Quinoxaline-2-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-3-fluoro-phenyl)-acid amides

Quinoxaline-2-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-the 4-fluorophenyl)-acid amides

Quinoxaline-2-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-4,5-dimethoxy-phenyl)-acid amides

Quinoline-3-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides

Quinoline-3-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-5-fluoro-phenyl)-acid amides

Quinoline-3-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-4-fluoro-phenyl)-acid amides

Quinoline-3-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-4,5-dimethoxy-phenyl)-acid amides

Quinoline-3-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-5-nitro-phenyl)-acid amides

Quinoline-3-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-4-methyl-phenyl)-acid amides

Quinoline-3-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-5-methyl-phenyl)-acid amides

Quinoline-3-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-4-chloro-phenyl)-acid amides

Quinoline-3-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-5-chloro-phenyl)-acid amides

Quinoline-3-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-5-amino-phenyl)-acid amides

Quinoline-2-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides

5,6,7,8-tetrahydroquinoline-3-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides

Pyridine-2-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides

N-(2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-niacinamide

N-(2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-Isonicotinamide

Pyrazine-2-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides

5-methyl-pyrazine-2-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides

N-(2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-6-methyl-niacinamide

N-(2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-6-methoxyl group-niacinamide

5-propionyl-pyrazine-2-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides

2-aminobenzoic amido-N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-phenyl }-benzamide

2-aminobenzoic amido-N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-phenyl }-5-methyl-benzamide

2-aminobenzoic amido-N-{4-[2-(6,7-dimethoxy-3,4-hydrogen-1H-isoquinoline 99.9-2-yl)-ethyl]-phenyl }-4-methyl-benzamide

2-aminobenzoic amido-N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-phenyl }-6-methyl-benzamide

2-(2-fluoro-aminobenzoic amido)-N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-phenyl }-benzamide

2-(3-fluoro-aminobenzoic amido)-N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-phenyl }-benzamide

2-(4-fluoro-aminobenzoic amido)-N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-phenyl }-benzamide

2-(2,4-two fluoro-aminobenzoyl amino)-N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-phenyl }-benzamide

2-(2,6-two fluoro-aminobenzoyl amino)-N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-phenyl }-benzamide

2-(2-chloro-aminobenzoic amido)-N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-phenyl }-benzamide

2-(3-chloro-aminobenzoic amido)-N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-phenyl }-benzamide

2-(4-chloro-aminobenzoic amido)-N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-phenyl }-benzamide

2-(2-methyl-aminobenzoic amido)-N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-phenyl }-benzamide

2-(3-methyl-aminobenzoic amido)-N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-phenyl }-benzamide

2-(4-methyl-aminobenzoic amido)-N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-phenyl }-benzamide

2-(2-methoxyl group-aminobenzoic amido)-N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-phenyl }-benzamide

2-(3-methoxyl group-aminobenzoic amido)-N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-phenyl }-benzamide

2-(4-methoxyl group-aminobenzoic amido)-N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-phenyl }-benzamide

2-(2-hydroxyl-aminobenzoic amido)-N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-phenyl }-benzamide

2-(3-hydroxyl-aminobenzoic amido)-N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-phenyl }-benzamide

2-(4-hydroxyl-aminobenzoic amido)-N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-phenyl }-benzamide

Acetate 2-(2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-the phenyl amino formyl radical)-phenylester

Acetate 3-(2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-the phenyl amino formyl radical) phenylester

Acetate 4-(2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-the phenyl amino formyl radical)-phenylester

2-(2-trifluoromethyl-aminobenzoic amido)-N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-phenyl }-benzamide

2-(3-trifluoromethyl-aminobenzoic amido)-N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-phenyl }-benzamide

2-(3-dimethylamino-aminobenzoic amido } N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-phenyl }-benzamide

2-(4-sec.-propyl-aminobenzoic amido)-N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-phenyl }-benzamide

2-(4-cyclohexyl-aminobenzoic amido)-N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-phenyl }-benzamide

Naphthalene-1-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides

Naphthalene-2-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides

2-(3,4-two chloro-aminobenzoyl amino)-N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-phenyl }-benzamide

2-(3,4-dimethyl-aminobenzoic amido)-N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-phenyl }-benzamide

Thiophene-2-carboxylic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides

Thiophene-3-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides

Furans-3-formic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides

The 1H-indole-2-carboxylic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides

Coumarilic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides

2-(4-cyclohexyl-aminobenzoic amido)-N-[3-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-propyl group]-benzamide

2-(4-cyclohexyl-aminobenzoic amido)-N-[2-(3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-benzamide

Quinoxaline-2-formic acid (2-{4-[3-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-propyl group]-the phenyl amino formyl radical }-phenyl)-acid amides

Quinoxaline-2-formic acid 2-[4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-ylmethyl) phenyl amino formyl radical]-phenyl)-acid amides

Quinoline-3-formic acid (2-{4-[2-(3,4-dihydro-1H-isoquinoline 99.9-2-yl) ethyl]-the phenyl amino formyl radical }-phenyl)-acid amides

Quinoline-3-formic acid 2-[4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-ylmethyl) phenyl amino formyl radical]-phenyl)-acid amides.

9. according to the compound of claim 1; it is that (6-{4-[2-(6 for quinoline-3-formic acid; 7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethyl]-the phenyl amino formyl radical }-benzo [1,3] dioxole-5-yl)-acid amides or its pharmacy acceptable salt.

10. medicinal or veterinary composition, it comprises carrier medicinal or for animals or thinner and as the compound of each definition among the claim 1-9 of activeconstituents.

11. prepare the method for the defined compound of claim 1, it comprises:

(a) with the aminobenzamide of formula (VI)

Wherein Ar, R ⁷And R ⁸Such as claim 1 definition, Z is with the lower section:

Wherein m, n, q, R, R ¹-R ⁶And X such as claim 1 definition, use formula R ⁹The carboxylic acid of-COOH or its reactive derivative are handled, wherein R ⁹Such as claim 1 definition; Or

(b) with formula XII compound:

Wherein Ar, R ⁵, R ⁶-R ⁹, X, q and m such as claim 1 definition, handle with the amine of formula XX:

Wherein R, R ¹-R ⁴With n such as claim 1 definition; And the protecting group of removable any optional existence if desired; and/or if desired; a kind of formula (I) compound can be changed into another kind of formula (I) compound and/or; if desired; a kind of formula (I) compound can be changed into its pharmacy acceptable salt and/or; if desired, salt can be changed into free formula (I) compound.

12. prepare the method for the defined compound of claim 6, it comprises:

(a) with formula VIII ' aminobenzamide

R wherein ³¹And R ⁴¹Such as claim 6 definition and optional protected, Z ' is with the lower section

Wherein r, s, R ¹¹And R ²¹Such as claim 6 definition, use formula R ⁵¹The carboxylic acid of-COOH or its activated derivatives are handled, wherein R ⁵¹Such as claim 6 definition; Or

(b) with formula XII ' compound:

R wherein ⁵¹Such as claim 6 definition, use the amine of formula IX ' to handle:

Wherein r, s, R ¹¹And R ²¹Such as claim 6 definition; Or

(c) with the azalactones of formula XIII ':

R wherein ⁵¹Define the samely, handle with the amine of formula (IX ')

Wherein r, s, R ¹¹And R ²¹Define the same; And the protecting group of removable any optional existence if desired; and/or if desired; a kind of formula (Ia) compound can be changed into another kind of formula (Ia) compound and/or; if desired; a kind of formula (Ia) compound can be changed into its pharmacy acceptable salt and/or; if desired, salt can be changed into free formula (Ia) compound.

13. the defined compound of claim 1 is preparing as the purposes in the medicine of P-gp inhibitor.

14. the purposes of claim 13, wherein said medicine is multiple drug-fast conditioning agent, strengthen the cytotoxicity of chemotherapeutics, enhancement is in the therapeutic action of the medicine of multiple resistance pathogenic agent, or the characteristic of clean absorption, distribution, metabolism or the elimination of increase medicine.